Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, a... more Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, and ischemia. Some studies proposed IL-4 and IL-13 as two important cytokines that are involved in late effects of ionizing radiation. On the other hand, these cytokines may, through upregulation of Duox1 and Duox2, induce chronic oxidative stress, inflammation, and fibrosis. In this study, we evaluated the upregulation of Duox1 and Duox2 pathways in hearts following chest irradiation in rats and then detected possible attenuation of them by melatonin. Materials and Methods: Twenty male Wistar rats were divided into four groups: (1) control; (2) melatonin treated (100 mg/kg); (3) radiation (15 Gy gamma rays); (4) melatonin treated before irradiation. All rats were sacrificed after 10 weeks and their heart tissues collected for real-time PCR (RT-PCR), ELISA detection of IL-4 and IL-13, as well as histopathological evaluation of macrophages and lymphocytes infiltration. Results: Results showed an upregulation of IL-4, IL4ra1, Duox1, and Duox2. The biggest changes were for IL4ra1 and Duox1. Treatment with melatonin before irradiation could attenuate the upregulation of all genes. Melatonin also caused a reduction in IL-4 as well as reverse infiltration of inflammatory cells. Conclusion: Duox1 and Duox2 may be involved in the late effects of radiation-induced heart injury. Also, via attenuation of these genes, melatonin can offer protection against the toxic effects of radiation on the heart.
Cancer is one of the most complicated diseases in present-day medical science. Yearly, several st... more Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radio-therapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.
Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in c... more Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radio-biology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregula-tion of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.
Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CS... more Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio-and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.
Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumor... more Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular en-dothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs-associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy.
Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play crit... more Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor micro-environment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers-instead, deploying mechanisms to retard tumor type-dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression.
Nanotechnology is a growing science that may provide several new applications for medicine, food ... more Nanotechnology is a growing science that may provide several new applications for medicine, food preservation, diagnostic technologies, and sanitation. Despite its beneficial applications, there are several questions related to the safety of nanomaterials for human use. The development of nanotechnology is associated with some concerns because of the increased risk of carcinogenesis following exposure to nanomaterials. The increased levels of reactive oxygen species (ROS) that are due to exposure to nanoparticles (NPs) are primarily responsible for the genotoxicity of metal NPs. Not all, but most metal NPs are able to directly produce free radicals through the release of metal ions and through interactions with water molecules. Furthermore, the increased production of free radicals and the cell death caused by metal NPs can stimulate reduction/oxidation (redox) reactions, leading to the continuous endogenous production of ROS in a positive feedback loop. The overexpression of in-flammatory mediators, such as NF-kB and STATs, the mitochondrial malfunction and the increased intracellular calcium levels mediate the chronic oxidative stress that occurs after exposure to metal NPs. In this paper, we review the genotoxicity of different types of metal NPs and the redox mechanisms that amplify the toxicity of these NPs.
Cancer is a disease of high complexity. Resistance to therapy is a major challenge in cancer targ... more Cancer is a disease of high complexity. Resistance to therapy is a major challenge in cancer targeted therapies. Overcoming this resistance requires a deep knowledge of the cellular interactions within tumor. Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are the main anti-cancer immune cells, while T regulatory cells (Tregs) and cancer associated fibroblasts (CAFs) facilitate immune escape of cancer cells. Melatonin is a natural agent with anti-cancer functions that has also been suggested as an adjuvant in combination with cancer therapy modalities such as chemotherapy, radiotherapy, immunotherapy and tumor vaccination. One of the main effects of melatonin is regulation of immune responses against cancer cells. Melatonin has been shown to potentiate the activities of anti-cancer immune cells, as well as attenuating the activities of Tregs and CAFs. It also has a potent effect on the mitochondria, which may change immune responses against cancer. In this review, we explain the mechanisms of immune regulation by melatonin involved in its anti-cancer effects.
Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This ... more Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This is the main issue, leading to several side effects to patients with abdominal cancers, in addition to affecting their quality of life. Epithelial layer and clonogenic cells in the jejunum are the most sensitive parts of the intestine, while damage to vascular may lead to chronic inflammation and bleeding. Both melatonin and metformin have shown abilities to attenuate radiation toxicities through the modulation of DNA damage responses, neutralization of free radicals and alleviation of inflammation. In this study, we aimed to evaluate the possible radioprotective effects of melatonin and metformin when administered either alone or as a combination, in rat's jejunum against a high dose of radiation. Method: 40 male rats were divided into 8 groups as G1: control; G2: metformin; G3: melatonin; G4: melatonin + metformin; G5: radiation; G6: radiation + melatonin; G7: radiation + metformin; G8: metformin + melatonin + radiation. Rats were irradiated with 10 Gy gamma rays, while treatments were administered at 100 mg/kg. The ratio for melatonin and metformin was 1:1. 3.5 days after irradiation, all rats were sacrificed, followed by histopathological evaluation of the jejunum. Results: This study showed that whole body irradiation of rats led to severe injuries to the epithelial and vascular of jejunum. A single administration of either melatonin or metformin was unable to mitigate radiation toxicity. However, administering the combination of melatonin and metformin could mildly mitigate radiation-induced jejunum injury. Conclusion: From the results of this study, we suggest that the combination of melatonin and metformin has superior radioprotective effect for jejunum compared with the single administration of these drugs.
Background: Radiotherapy is a commonly used cancer treatment modality. However, radiation-induced... more Background: Radiotherapy is a commonly used cancer treatment modality. However, radiation-induced complications are major drawbacks, especially at high doses. Radiation-induced brachial plexopathy (RIBP) is mostly observed in breast and lung cancer patients some months to years after radiotherapy. RIBP symptoms have negative effects on patients' quality of life. The aim of this study was to review RIBP according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Research Methodology: Online databases (PubMed, Scopus, Web of Science and Embase) were searched to retrieve relevant studies on brachial plexopathy as a complication of radiotherapy. Results: Initial search results yielded a total of 657 articles. After careful screening of their titles and abstracts, according to the inclusion and exclusion criteria, 31 articles were finally included in this study. Findings from these 31 papers showed that a total of 9192 cancer patients had undergone radiotherapy for different regions including chest, axillary area, thoracic outlet, neck and breast. 26.4 % of these patients had RIPB (associated with symptoms such as paresthesia, pain, weakness, and/or motor dysfunction, organ pathology/dysfunction etc.) with different follow up times, where 8.2% of patients had RIPB after a mean time of 1.2 years, 15.8 % after 2.6 years, 51% after 5 years, 14 % after 7.8 years, and 11% after 10.5 years. Conclusion: From our findings, we can conclude that the issue of radiation-induced brachial plexus complication in human is of great concern. Common symptoms associated with this complication include paresthesia, numbness, pain and weakness. We recommend the use of individual dose planning and computer-assisted image segmentation techniques that support rapid and reliable contouring of the brachial plexus. Also, the radiation dose to the brachial plexus should be limited as much as possible to reduce the risk of brachial plexopathy.
Background: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest ... more Background: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest radiotherapy. They result from massive and chronic production of reactive oxygen species (ROS), inhibition of antioxidant enzymes as well as the release of several inflammatory mediators. In this study, we aimed to detect the radioprotective effects of metformin (as inhibitor of mi-tochondrial ROS), resveratrol (as stimulator of antioxidant defense enzymes) and alpha-lipoic acid (as direct antioxidant) for alleviating radiation-induced pneumonitis and fibrosis.
Purpose
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific a... more Purpose
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy.
Results
Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior.
Conclusion
Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.
Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within ... more Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor.
INTRODUCTION: Since the survival time of patients with bony metastases has noticeably improved in... more INTRODUCTION: Since the survival time of patients with bony metastases has noticeably improved in recent years, these patients are at high risk of complications associated with this metastasis. Hence, the appropriate choice of treatment modality or combination of therapeutic approaches can lead to increasing bone pain relief, improving quality of life, etc. This study is aimed to evaluate the effectiveness of combined radiotherapy and hyperthermia for the treatment response of patients with painful bony metastases. PATIENTS AND METHODS: In a single-arm clinical trial, 23 eligible patients (14 female and 9 male) with the mean age of 67 years old and suffering from bony metastases were enrolled in the study. Two hours after radiotherapy, the patients underwent hyperthermia for 1 h in the supine position. All the patients completed the brief pain inventory (BPI) assessment tool and quality of life questionnaire (QLQ-C30) from the European Organization for Research and Treatment of Cancer (EORTC) at the baseline, end of the treatment and 1, 2 and 3 months thereafter. The response to the treatment was assessed as the zero score (complete response) or two or more than two-point drop of the worst pain within the preceding 24 h (partial response) during the 3-month posttreatment. RESULTS: All the pain intensity and interference scores, except the pain interference with the enjoyment of life score, significantly decreased. A total of 18 out of 23 patients (78%) achieved complete or partial response. The number of patients using pain relief medications decreased from 74% (n=17) at the baseline to 48% (n=11) 3 months later. Moreover, except for nausea and vomiting, appetite loss, diarrhea and financial impact problems, the patients' quality of life improved significantly in all the functional scales and symptoms within 3 months. CONCLUSION: This study showed that using hyperthermia in combination with radiotherapy significantly ameliorated bone pain among the patients suffering from cancer with painful bony metastases.
Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and lat... more Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and late side effects on normal tissues, which is a burden for delivery of a high dose of radiation or drugs on tumor cells. In addition, tumor cells achieve adaptive responses to subsequent doses of radiation and chemotherapy, leading to tumor resistance and accelerated repopulation. Resistance to radiotherapy and chemotherapy can occur following adaptive responses, which itself is due to the release of large numbers of inter- and intracellular mediators by immune cells as well as other tumor microenvironment (TME) cells. Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy. Furthermore, in some cancer cells, melatonin aids sensitizing cancer cells to therapy. Apoptosis is one of the main mechanisms of cell death following exposure to radiation and chemotherapy. Evidences have shown a direct relation between apoptosis induction in tumor cells with increased tumor delay regression and survival. Melatonin through modulation of several apoptosis mediators such as mitochondria, Bax, Bcl-2, endogenous ROS, and apoptosis receptors facilitate apoptosis. The current review aims to explain mechanisms of apoptosis induction following exposure to radiation and chemotherapy drugs. We also reviewed the modulatory effect of melatonin on apoptosis signaling pathways.
Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumor... more Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular en-dothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs-associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy.
Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play crit... more Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor micro-environment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers-instead, deploying mechanisms to retard tumor type-dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression.
BACKGROUND: Chemotherapy, as a systemic therapy, is one of the most effective modalities for canc... more BACKGROUND: Chemotherapy, as a systemic therapy, is one of the most effective modalities for cancer treatment. However, the use of chemotherapeutic drugs in patients with breast cancer can lead to thyroid dysfunction. This systematic review summarizes the available data on thyroid function following breast cancer chemotherapy. METHODS: To illuminate the thyroid toxicities induced by different chemotherapy regimens in patients with breast cancer, a systematic search was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in Scopus, Embase, PubMed and Web of Science electronic databases up to December 2018. On the basis of a set of prespecified inclusion and exclusion criteria, eight eligible articles providing data on thyroid function following chemotherapy in patients with breast cancer were included in the study. RESULTS: According to the obtained results, it was found that for most cases, the levels of triiodothyronine (T3), free T3 (FT3), thyroxin (T4) and free T4 (FT4) hormones decrease following breast cancer chemotherapy regimens used in these eligible studies. However, alteration of thyroid-stimulating hormone (TSH) level after breast cancer chemotherapy was not clear. CONCLUSION: The findings showed that thyroid function and TSH hormone level can change in patients with breast cancer receiving different chemotherapy regimens.
Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, a... more Background: Radiation-induced heart injury can lead to increased risk of heart failure, attack, and ischemia. Some studies proposed IL-4 and IL-13 as two important cytokines that are involved in late effects of ionizing radiation. On the other hand, these cytokines may, through upregulation of Duox1 and Duox2, induce chronic oxidative stress, inflammation, and fibrosis. In this study, we evaluated the upregulation of Duox1 and Duox2 pathways in hearts following chest irradiation in rats and then detected possible attenuation of them by melatonin. Materials and Methods: Twenty male Wistar rats were divided into four groups: (1) control; (2) melatonin treated (100 mg/kg); (3) radiation (15 Gy gamma rays); (4) melatonin treated before irradiation. All rats were sacrificed after 10 weeks and their heart tissues collected for real-time PCR (RT-PCR), ELISA detection of IL-4 and IL-13, as well as histopathological evaluation of macrophages and lymphocytes infiltration. Results: Results showed an upregulation of IL-4, IL4ra1, Duox1, and Duox2. The biggest changes were for IL4ra1 and Duox1. Treatment with melatonin before irradiation could attenuate the upregulation of all genes. Melatonin also caused a reduction in IL-4 as well as reverse infiltration of inflammatory cells. Conclusion: Duox1 and Duox2 may be involved in the late effects of radiation-induced heart injury. Also, via attenuation of these genes, melatonin can offer protection against the toxic effects of radiation on the heart.
Cancer is one of the most complicated diseases in present-day medical science. Yearly, several st... more Cancer is one of the most complicated diseases in present-day medical science. Yearly, several studies suggest various strategies for preventing carcinogenesis. Furthermore, experiments for the treatment of cancer with low side effects are ongoing. Chemotherapy, targeted therapy, radio-therapy and immunotherapy are the most common non-invasive strategies for cancer treatment. One of the most challenging issues encountered with these modalities is low effectiveness, as well as normal tissue toxicity for chemo-radiation therapy. The use of some agents as adjuvants has been suggested to improve tumor responses and also alleviate normal tissue toxicity. Resveratrol, a natural flavonoid, has attracted a lot of attention for the management of both tumor and normal tissue responses to various modalities of cancer therapy. As an antioxidant and anti-inflammatory agent, in vitro and in vivo studies show that it is able to mitigate chemo-radiation toxicity in normal tissues. However, clinical studies to confirm the usage of resveratrol as a chemo-radioprotector are lacking. In addition, it can sensitize various types of cancer cells to both chemotherapy drugs and radiation. In recent years, some clinical studies suggested that resveratrol may have an effect on inducing cancer cell killing. Yet, clinical translation of resveratrol has not yielded desirable results for the combination of resveratrol with radiotherapy, targeted therapy or immunotherapy. In this paper, we review the potential role of resveratrol for preserving normal tissues and sensitization of cancer cells in combination with different cancer treatment modalities.
Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in c... more Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radio-biology. Investigations in recent decades have suggested potential targets that are involved in the protection against radiation-induced damages to normal tissues and can be proposed for mitigation of radiation injury. Emerging evidences have been shown to be in contrast to an old dogma in radiation biology; a major amount of reactive oxygen species (ROS) production and cell toxicity occur during some hours to years after exposure to ionizing radiation. This can be attributed to upregula-tion of inflammatory and fibrosis mediators, epigenetic changes and disruption of the normal metabolism of oxygen. In the current review, we explain the cellular and molecular changes following exposure of normal tissues to ionizing radiation. Furthermore, we review potential targets that can be proposed for protection and mitigation of radiation toxicity.
Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CS... more Cancer stem cells (CSCs) are a population of self-renewal cells with high tumorigenic potency. CSCs can adopt easily with changes in the nearby milieu, and are more resistant to conventional therapies than other cells within a tumor. CSC resistance can be induced secondary to radio-and chemotherapy, or even after chemotherapy secession. A combination of both intrinsic and extrinsic factors is contributed to CSC-mediated therapy resistance. CSCs represent protective autophagy and efficient cell cycling, along with highly qualified epithelial-mesenchymal transition (EMT) regulators, reactive oxygen species (ROS) scavengers, drug transporters, and anti-apoptotic and DNA repairing systems. In addition, CSCs develop cross-talking and share some characteristics with other cells within the tumor microenvironment (TME) being more intense in higher stage tumors, and thereby sophisticating tumor-targeted therapies. TME, in fact, is a nest for aggravating resistance mechanisms in CSCs. TME is exposed constantly to the nutritional, metabolic and oxygen deprivation; these conditions promote CSC adaptation. This review is aimed to discuss main (intrinsic and extrinsic) mechanisms of CSC resistance and suggest some strategies to revoke this important promoter of therapy failure.
Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumor... more Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular en-dothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs-associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy.
Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play crit... more Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor micro-environment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers-instead, deploying mechanisms to retard tumor type-dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression.
Nanotechnology is a growing science that may provide several new applications for medicine, food ... more Nanotechnology is a growing science that may provide several new applications for medicine, food preservation, diagnostic technologies, and sanitation. Despite its beneficial applications, there are several questions related to the safety of nanomaterials for human use. The development of nanotechnology is associated with some concerns because of the increased risk of carcinogenesis following exposure to nanomaterials. The increased levels of reactive oxygen species (ROS) that are due to exposure to nanoparticles (NPs) are primarily responsible for the genotoxicity of metal NPs. Not all, but most metal NPs are able to directly produce free radicals through the release of metal ions and through interactions with water molecules. Furthermore, the increased production of free radicals and the cell death caused by metal NPs can stimulate reduction/oxidation (redox) reactions, leading to the continuous endogenous production of ROS in a positive feedback loop. The overexpression of in-flammatory mediators, such as NF-kB and STATs, the mitochondrial malfunction and the increased intracellular calcium levels mediate the chronic oxidative stress that occurs after exposure to metal NPs. In this paper, we review the genotoxicity of different types of metal NPs and the redox mechanisms that amplify the toxicity of these NPs.
Cancer is a disease of high complexity. Resistance to therapy is a major challenge in cancer targ... more Cancer is a disease of high complexity. Resistance to therapy is a major challenge in cancer targeted therapies. Overcoming this resistance requires a deep knowledge of the cellular interactions within tumor. Natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) are the main anti-cancer immune cells, while T regulatory cells (Tregs) and cancer associated fibroblasts (CAFs) facilitate immune escape of cancer cells. Melatonin is a natural agent with anti-cancer functions that has also been suggested as an adjuvant in combination with cancer therapy modalities such as chemotherapy, radiotherapy, immunotherapy and tumor vaccination. One of the main effects of melatonin is regulation of immune responses against cancer cells. Melatonin has been shown to potentiate the activities of anti-cancer immune cells, as well as attenuating the activities of Tregs and CAFs. It also has a potent effect on the mitochondria, which may change immune responses against cancer. In this review, we explain the mechanisms of immune regulation by melatonin involved in its anti-cancer effects.
Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This ... more Background: Jejunum is one of the most radiosensitive parts of the gastrointestinal system. This is the main issue, leading to several side effects to patients with abdominal cancers, in addition to affecting their quality of life. Epithelial layer and clonogenic cells in the jejunum are the most sensitive parts of the intestine, while damage to vascular may lead to chronic inflammation and bleeding. Both melatonin and metformin have shown abilities to attenuate radiation toxicities through the modulation of DNA damage responses, neutralization of free radicals and alleviation of inflammation. In this study, we aimed to evaluate the possible radioprotective effects of melatonin and metformin when administered either alone or as a combination, in rat's jejunum against a high dose of radiation. Method: 40 male rats were divided into 8 groups as G1: control; G2: metformin; G3: melatonin; G4: melatonin + metformin; G5: radiation; G6: radiation + melatonin; G7: radiation + metformin; G8: metformin + melatonin + radiation. Rats were irradiated with 10 Gy gamma rays, while treatments were administered at 100 mg/kg. The ratio for melatonin and metformin was 1:1. 3.5 days after irradiation, all rats were sacrificed, followed by histopathological evaluation of the jejunum. Results: This study showed that whole body irradiation of rats led to severe injuries to the epithelial and vascular of jejunum. A single administration of either melatonin or metformin was unable to mitigate radiation toxicity. However, administering the combination of melatonin and metformin could mildly mitigate radiation-induced jejunum injury. Conclusion: From the results of this study, we suggest that the combination of melatonin and metformin has superior radioprotective effect for jejunum compared with the single administration of these drugs.
Background: Radiotherapy is a commonly used cancer treatment modality. However, radiation-induced... more Background: Radiotherapy is a commonly used cancer treatment modality. However, radiation-induced complications are major drawbacks, especially at high doses. Radiation-induced brachial plexopathy (RIBP) is mostly observed in breast and lung cancer patients some months to years after radiotherapy. RIBP symptoms have negative effects on patients' quality of life. The aim of this study was to review RIBP according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Research Methodology: Online databases (PubMed, Scopus, Web of Science and Embase) were searched to retrieve relevant studies on brachial plexopathy as a complication of radiotherapy. Results: Initial search results yielded a total of 657 articles. After careful screening of their titles and abstracts, according to the inclusion and exclusion criteria, 31 articles were finally included in this study. Findings from these 31 papers showed that a total of 9192 cancer patients had undergone radiotherapy for different regions including chest, axillary area, thoracic outlet, neck and breast. 26.4 % of these patients had RIPB (associated with symptoms such as paresthesia, pain, weakness, and/or motor dysfunction, organ pathology/dysfunction etc.) with different follow up times, where 8.2% of patients had RIPB after a mean time of 1.2 years, 15.8 % after 2.6 years, 51% after 5 years, 14 % after 7.8 years, and 11% after 10.5 years. Conclusion: From our findings, we can conclude that the issue of radiation-induced brachial plexus complication in human is of great concern. Common symptoms associated with this complication include paresthesia, numbness, pain and weakness. We recommend the use of individual dose planning and computer-assisted image segmentation techniques that support rapid and reliable contouring of the brachial plexus. Also, the radiation dose to the brachial plexus should be limited as much as possible to reduce the risk of brachial plexopathy.
Background: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest ... more Background: Radiation-induced pneumonitis and fibrosis are the most common side effects of chest radiotherapy. They result from massive and chronic production of reactive oxygen species (ROS), inhibition of antioxidant enzymes as well as the release of several inflammatory mediators. In this study, we aimed to detect the radioprotective effects of metformin (as inhibitor of mi-tochondrial ROS), resveratrol (as stimulator of antioxidant defense enzymes) and alpha-lipoic acid (as direct antioxidant) for alleviating radiation-induced pneumonitis and fibrosis.
Purpose
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific a... more Purpose
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy.
Results
Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior.
Conclusion
Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.
Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within ... more Cancer associated fibroblasts (CAFs) as the dominant, long-lived and highly plastic cells within the tumor microenvironment (TME) with multi-faceted roles that are endowed with tumor aggressive features. They can instruct and shape the stroma of tumor into being a highly qualified bed for cellular recruitment, differentiation and plasticity in the host tissue or secondary organ/s. In this Review, we have a discussion over CAF reprogramming as a general concept, inducers and outcomes, pursued by suggesting potential strategies to combat this key promoter of tumor.
INTRODUCTION: Since the survival time of patients with bony metastases has noticeably improved in... more INTRODUCTION: Since the survival time of patients with bony metastases has noticeably improved in recent years, these patients are at high risk of complications associated with this metastasis. Hence, the appropriate choice of treatment modality or combination of therapeutic approaches can lead to increasing bone pain relief, improving quality of life, etc. This study is aimed to evaluate the effectiveness of combined radiotherapy and hyperthermia for the treatment response of patients with painful bony metastases. PATIENTS AND METHODS: In a single-arm clinical trial, 23 eligible patients (14 female and 9 male) with the mean age of 67 years old and suffering from bony metastases were enrolled in the study. Two hours after radiotherapy, the patients underwent hyperthermia for 1 h in the supine position. All the patients completed the brief pain inventory (BPI) assessment tool and quality of life questionnaire (QLQ-C30) from the European Organization for Research and Treatment of Cancer (EORTC) at the baseline, end of the treatment and 1, 2 and 3 months thereafter. The response to the treatment was assessed as the zero score (complete response) or two or more than two-point drop of the worst pain within the preceding 24 h (partial response) during the 3-month posttreatment. RESULTS: All the pain intensity and interference scores, except the pain interference with the enjoyment of life score, significantly decreased. A total of 18 out of 23 patients (78%) achieved complete or partial response. The number of patients using pain relief medications decreased from 74% (n=17) at the baseline to 48% (n=11) 3 months later. Moreover, except for nausea and vomiting, appetite loss, diarrhea and financial impact problems, the patients' quality of life improved significantly in all the functional scales and symptoms within 3 months. CONCLUSION: This study showed that using hyperthermia in combination with radiotherapy significantly ameliorated bone pain among the patients suffering from cancer with painful bony metastases.
Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and lat... more Radio- and chemotherapy are the most common cancer treatment modalities. They cause acute and late side effects on normal tissues, which is a burden for delivery of a high dose of radiation or drugs on tumor cells. In addition, tumor cells achieve adaptive responses to subsequent doses of radiation and chemotherapy, leading to tumor resistance and accelerated repopulation. Resistance to radiotherapy and chemotherapy can occur following adaptive responses, which itself is due to the release of large numbers of inter- and intracellular mediators by immune cells as well as other tumor microenvironment (TME) cells. Melatonin is a potent natural antioxidant and anti-inflammatory agent that protects against toxic side effects of radiation and chemotherapy. Furthermore, in some cancer cells, melatonin aids sensitizing cancer cells to therapy. Apoptosis is one of the main mechanisms of cell death following exposure to radiation and chemotherapy. Evidences have shown a direct relation between apoptosis induction in tumor cells with increased tumor delay regression and survival. Melatonin through modulation of several apoptosis mediators such as mitochondria, Bax, Bcl-2, endogenous ROS, and apoptosis receptors facilitate apoptosis. The current review aims to explain mechanisms of apoptosis induction following exposure to radiation and chemotherapy drugs. We also reviewed the modulatory effect of melatonin on apoptosis signaling pathways.
Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumor... more Radiotherapy is one of the most common treatment modalities for controlling a wide range of tumors. However, it has been shown that radiotherapy alone is unable to completely eradicate some tumors and could be associated with a high possibility of tumor recurrence. To date, various experimental and clinical studies have been conducted to explore some efficient targets within tumor microenvironment (TME) to enhance tumor response to radiotherapy; thus help eliminate or eradicate tumors. Although targeting DNA damage responses (DDRs) is associated with severe toxicities, studies in recent decade suggest that inhibition of some apoptosis/survival targets within TME is promising. This is also associated with changes in the numbers of T regulatory cells (Tregs) and cytotoxic T lymphocytes (CTLs). The inhibition of cyclooxygenase-2 (COX-2), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), mitogen-activated protein kinases (MAPKs) and vascular en-dothelial growth factor (VEGF) have also shown promising results. The combination of receptor tyrosine kinase (RTK) inhibitors with radiotherapy is interesting as well as the clinical use of some drugs and antibodies. Epidermal growth factor receptor (EGFR) inhibitors are the most common RTK inhibitors. Some clinical trials in recent years have shown very interesting results for immune checkpoint inhibitors (ICIs), especially programmed death-ligand 1 (PD-L1) and CTLs-associated antigen 4 (CTLA-4) inhibitors. It has been suggested that administration of ICIs during or after hypofractionated radiotherapy could lead to best results. In this review, we explain TME response to radiotherapy and potential targets for sensitization of cancer cells to radiotherapy.
Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play crit... more Cancer stem cells (CSCs) are self-renewal population localized within cancer niches and play critical roles in tumor initiation, recurrence and metastasis. Despite extensive research, challenges about identity of CSCs and combating them in cancer therapy still remain steady. Cellular plasticity is a cardinal feature of tumor micro-environment (TME) tremendously influencing tumor aggressive behavior. Plasticity and CSC a (symmetry) are interconnecting processes essential for shaping a cancer through nurturing a wide number of cells with tumor promoting capacities. The plastic nature of TME cellularity infers that destemming just CSCs is not sufficient in respect with therapy, especially for high-grade cancers-instead, deploying mechanisms to retard tumor type-dependent TME-CSC interplay is a suggested strategy for making a durable remission of cancer. This requires extending our understanding about CSC divisional profiling and plasticity in order to find critical drivers in cancer progression.
BACKGROUND: Chemotherapy, as a systemic therapy, is one of the most effective modalities for canc... more BACKGROUND: Chemotherapy, as a systemic therapy, is one of the most effective modalities for cancer treatment. However, the use of chemotherapeutic drugs in patients with breast cancer can lead to thyroid dysfunction. This systematic review summarizes the available data on thyroid function following breast cancer chemotherapy. METHODS: To illuminate the thyroid toxicities induced by different chemotherapy regimens in patients with breast cancer, a systematic search was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in Scopus, Embase, PubMed and Web of Science electronic databases up to December 2018. On the basis of a set of prespecified inclusion and exclusion criteria, eight eligible articles providing data on thyroid function following chemotherapy in patients with breast cancer were included in the study. RESULTS: According to the obtained results, it was found that for most cases, the levels of triiodothyronine (T3), free T3 (FT3), thyroxin (T4) and free T4 (FT4) hormones decrease following breast cancer chemotherapy regimens used in these eligible studies. However, alteration of thyroid-stimulating hormone (TSH) level after breast cancer chemotherapy was not clear. CONCLUSION: The findings showed that thyroid function and TSH hormone level can change in patients with breast cancer receiving different chemotherapy regimens.
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Papers by Masoud Najafi
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy.
Results
Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior.
Conclusion
Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.
PATIENTS AND METHODS: In a single-arm clinical trial, 23 eligible patients (14 female and 9 male) with the mean age of 67 years old and suffering from bony metastases were enrolled in the study. Two hours after radiotherapy, the patients underwent hyperthermia for 1 h in the supine position. All the patients completed the brief pain inventory (BPI) assessment tool and quality of life questionnaire (QLQ-C30) from the European Organization for Research and Treatment of Cancer (EORTC) at the baseline, end of the treatment and 1, 2 and 3 months thereafter. The response to the treatment was assessed as the zero score (complete response) or two or more than two-point drop of the worst pain within the preceding 24 h (partial response) during the 3-month posttreatment.
RESULTS: All the pain intensity and interference scores, except the pain interference with the enjoyment of life score, significantly decreased. A total of 18 out of 23 patients (78%) achieved complete or partial response. The number of patients using pain relief medications decreased from 74% (n=17) at the baseline to 48% (n=11) 3 months later. Moreover, except for nausea and vomiting, appetite loss, diarrhea and financial impact problems, the patients' quality of life improved significantly in all the functional scales and symptoms within 3 months.
CONCLUSION: This study showed that using hyperthermia in combination with radiotherapy significantly ameliorated bone pain among the patients suffering from cancer with painful bony metastases.
METHODS: To illuminate the thyroid toxicities induced by different chemotherapy regimens in patients with breast cancer, a systematic search was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in Scopus, Embase, PubMed and Web of Science electronic databases up to December 2018. On the basis of a set of prespecified inclusion and exclusion criteria, eight eligible articles providing data on thyroid function following chemotherapy in patients with breast cancer were included in the study.
RESULTS: According to the obtained results, it was found that for most cases, the levels of triiodothyronine (T3), free T3 (FT3), thyroxin (T4) and free T4 (FT4) hormones decrease following breast cancer chemotherapy regimens used in these eligible studies. However, alteration of thyroid-stimulating hormone (TSH) level after breast cancer chemotherapy was not clear.
CONCLUSION: The findings showed that thyroid function and TSH hormone level can change in patients with breast cancer receiving different chemotherapy regimens.
Cancer stem cells (CSCs) are highly tumorigenic cell types that reside within specific areas of tumor microenvironment (TME), and are endowed with self-renewal and resistance properties. Here, we aimed to discuss mechanisms involved in hypoxia-derived CSC resistance and targeting for effective cancer therapy.
Results
Preferential localization within hypoxic niches would help CSCs develop adaptive mechanisms, mediated through the modification of responses to various stressors and, as a result, show a more aggressive behavior.
Conclusion
Hypoxia, in fact, serves as a multi-tasking strategy to nurture CSCs with this adaptive capacity, complexing targeted therapies.
PATIENTS AND METHODS: In a single-arm clinical trial, 23 eligible patients (14 female and 9 male) with the mean age of 67 years old and suffering from bony metastases were enrolled in the study. Two hours after radiotherapy, the patients underwent hyperthermia for 1 h in the supine position. All the patients completed the brief pain inventory (BPI) assessment tool and quality of life questionnaire (QLQ-C30) from the European Organization for Research and Treatment of Cancer (EORTC) at the baseline, end of the treatment and 1, 2 and 3 months thereafter. The response to the treatment was assessed as the zero score (complete response) or two or more than two-point drop of the worst pain within the preceding 24 h (partial response) during the 3-month posttreatment.
RESULTS: All the pain intensity and interference scores, except the pain interference with the enjoyment of life score, significantly decreased. A total of 18 out of 23 patients (78%) achieved complete or partial response. The number of patients using pain relief medications decreased from 74% (n=17) at the baseline to 48% (n=11) 3 months later. Moreover, except for nausea and vomiting, appetite loss, diarrhea and financial impact problems, the patients' quality of life improved significantly in all the functional scales and symptoms within 3 months.
CONCLUSION: This study showed that using hyperthermia in combination with radiotherapy significantly ameliorated bone pain among the patients suffering from cancer with painful bony metastases.
METHODS: To illuminate the thyroid toxicities induced by different chemotherapy regimens in patients with breast cancer, a systematic search was done in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in Scopus, Embase, PubMed and Web of Science electronic databases up to December 2018. On the basis of a set of prespecified inclusion and exclusion criteria, eight eligible articles providing data on thyroid function following chemotherapy in patients with breast cancer were included in the study.
RESULTS: According to the obtained results, it was found that for most cases, the levels of triiodothyronine (T3), free T3 (FT3), thyroxin (T4) and free T4 (FT4) hormones decrease following breast cancer chemotherapy regimens used in these eligible studies. However, alteration of thyroid-stimulating hormone (TSH) level after breast cancer chemotherapy was not clear.
CONCLUSION: The findings showed that thyroid function and TSH hormone level can change in patients with breast cancer receiving different chemotherapy regimens.