Cancer stem cells (CSCs) in cancer progression and therapy

Cancer stem cells (CSCs) are self-renewable cell types that are identified in most types of liquid and solid cancers and contributed to tumor onset, expansion, resistance, recurrence, and metastasis after therapy. CSCs are identified from the expression of cell surface markers, which is tumor-type dependent. The transition between CSCs with cancer cells and other non-CSCs occurs in cancers, which is possibly under the control of signals from CSCs and tumor microenvironment (TME), including CSC niche. Cancer-associated fibroblasts are among the most influential cells for promoting both differentiation of CSCs and dedifferentiation of non-CSCs toward attaining a CSC-like phenotype. WNT/β-catenin, transforming growth factor-β, Hedgehog, and Notch are important signals for maintaining self-renewal in CSCs. An effective therapeutic strategy relies on targeting both CSCs and non-CSCs to remove a possible chance of tumor relapse. There are multiple ways to target CSCs, including immunotherapy, hormone therapy, (mi)siRNA delivery, and gene knockout. Such approaches can be designed for suppressing CSC stemness, tumorigenic cues from TME, CSC extrinsic and/or intrinsic signaling, hypoxia or for promoting differentiation in the cells. Because of sharing a range of characteristics to normal stem/progenitor cells, CSCs must be targeted based on their unique markers and their preferential expression of antigens. © 2018 Wiley Periodicals, Inc

The role of melatonin on doxorubicin-induced cardiotoxicity: A systematic review

Purpose: Doxorubicin, as an effective chemotherapeutic drug, is commonly used for combating various solid and hematological tumors. However, doxorubicin-induced cardiotoxicity is considered as a serious adverse effect, and it limits the clinical use of this chemotherapeutic drug. The use of melatonin can lead to a decrease in the cardiotoxic effect induced by doxorubicin. The aim of this review was to evaluate the potential role of melatonin in the prevention of doxorubicin-induced cardiotoxicity. Methods: This review was conducted by a full systematic search strategy based on PRISMA guidelines for the identification of relevant literature in the electronic databases of PubMed, Web of Science, Embase, and Scopus up to January 2019 using search terms in the titles and abstracts. 286 articles were screened in accordance with our inclusion and exclusion criteria. Finally, 28 articles were selected in this systematic review. Results: The findings demonstrated that doxorubicin-treated groups had increased mortality, decreased body weight and heart weight, and increased ascites compared to the control groups; the co-administration of melatonin revealed an opposite pattern compared to the doxorubicin-treated groups. Also, this chemotherapeutic agent can lead to biochemical and histopathological changes; as for most of the cases, these alterations were reversed near to normal levels (control groups) by melatonin co-administration. Melatonin exerts these protection effects through mechanisms of anti-oxidant, anti-apoptosis, anti-inflammatory, and mitochondrial function. Conclusion: The results of this systematic review indicated that co-administration of melatonin ameliorates the doxorubicin-induced cardiotoxicity. © 2019 Elsevier Inc

Disruption of the redox balance with either oxidative or anti-oxidative overloading as a promising target for cancer therapy

Abstract Oxidative stress acts as a double edged sword by being both a promoter and a suppressor of cancer. Moderate oxidative stress is beneficial for cancer cell proliferative and invasiveness features, while overexposure of the cells to oxidative insults could induce cancer cell apoptosis and reduce hypoxia along with modulating the immune system for regression of tumor. Cancer cells and cancer stem cells have highly efficient redox systems that make them resistant to oxidative insults. The redox disruptive approach is an area of current research and key for oxidative targeted cancer therapies. This disruption is applicable by using either oxidative or anti oxidative overloading strategies, specifically on cancer cells without influencing normal cells or tissues around tumor. The activity of tumor suppressor cells within tumor microenvironment is needed to be maintained in patients receiving such approaches. KEYWORDS: cancer, oxidative stress, reactive oxygen species (ROS), redo

Boosting immune system against cancer by melatonin: A mechanistic viewpoint

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. © 2019 Elsevier Inc

Cyclooxygenase-2 in cancer: A review

Cyclooxygenase-2 (COX-2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo- and radiotherapy. COX-2 is released by cancer-associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX-2 induces cancer stem cell (CSC)-like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX-2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX-2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX-2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX-2 on cancer cells or its regulation. Members of mitogen-activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor-κβ are main upstream modulators for COX-2 in cancer cells. COX-2 also has interactions with a number of hormones within the body. Inhibition of COX-2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX-2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX-2 inhibition also sensitizes cancer cells to treatments like radio- and chemotherapy. Chemotherapeutic agents adversely induce COX-2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX-2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer. © 2018 Wiley Periodicals, Inc

Targets for improving tumor response to radiotherapy

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 endothelial 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. © 2019 Elsevier B.V

Metformin as a Radiation Modifier; Implications to Normal Tissue Protection and Tumor Sensitization

BACKGROUND: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy. CONCLUSION: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster. Copyright© Bentham Science Publishers; For any queries, please email at [email protected]

Melatonin and cancer: From the promotion of genomic stability to use in cancer treatment

Cancer remains among the most challenging human diseases. Several lines of evidence suggest that carcinogenesis is a complex process that is initiated by DNA damage. Exposure to clastogenic agents such as heavy metals, ionizing radiation (IR), and chemotherapy drugs may cause chronic mutations in the genomic material, leading to a phenomenon named genomic instability. Evidence suggests that genomic instability is responsible for cancer incidence after exposure to carcinogenic agents, and increases the risk of secondary cancers following treatment with radiotherapy or chemotherapy. Melatonin as the main product of the pineal gland is a promising hormone for preventing cancer and improving cancer treatment. Melatonin can directly neutralize toxic free radicals more efficiently compared with other classical antioxidants. In addition, melatonin is able to regulate the reduction/oxidation (redox) system in stress conditions. Through regulation of mitochondrial nction and inhibition of pro-oxidant enzymes, melatonin suppresses chronic oxidative stress. Moreover, melatonin potently stimulates DNA damage responses that increase the tolerance of normal tissues to toxic effect of IR and may reduce the risk of genomic instability in patients who undergo radiotherapy. Through these mechanisms, melatonin attenuates several side effects of radiotherapy and chemotherapy. Interestingly, melatonin has shown some synergistic properties with IR and chemotherapy, which is distinct from classical antioxidants that are mainly used for the alleviation of adverse events of radiotherapy and chemotherapy. In this review, we describe the anticarcinogenic effects of melatonin and also its possible application in clinical oncology. © 2018 Wiley Periodicals, Inc

Modulation of apoptosis by melatonin for improving cancer treatment efficiency: An updated review

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. © 2019 Elsevier Inc

NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy

Background: Radiotherapy is a treatment modality for cancer. For better therapeutic efficiency, it could be used in combination with surgery, chemotherapy or immunotherapy. In addition to its beneficial therapeutic effects, exposure to radiation leads to several toxic effects on normal tissues. Also, it may induce some changes in genomic expression of tumor cells, thereby increasing the resistance of tumor cells. These changes lead to the appearance of some acute reactions in irradiated organs, increased risk of carcinogenesis, and reduction in the therapeutic effect of radiotherapy. Discussion: So far, several studies have proposed different targets such as cyclooxygenase-2 (COX-2), some toll-like receptors (TLRs), mitogen-activated protein kinases (MAPKs) etc., for the amelioration of radiation toxicity and enhancing tumor response. NADPH oxidase includes five NOX and two dual oxidases (DUOX1 and DUOX2) subfamilies that through the production of superoxide and hydrogen peroxide, play key roles in oxidative stress and several signaling pathways involved in early and late effects of ionizing radiation. Chronic ROS production by NOX enzymes can induce genomic instability, thereby increasing the risk of carcinogenesis. Also, these enzymes are able to induce cell death, especially through apoptosis and senescence that may affect tissue function. ROS-derived NADPH oxidase causes apoptosis in some organs such as intestine and tongue, which mediate inflammation. Furthermore, continuous ROS production stimulates fibrosis via stimulation of fibroblast differentiation and collagen deposition. Evidence has shown that in contrast to normal tissues, the NOX system induces tumor resistance to radiotherapy through some mechanisms such as induction of hypoxia, stimulation of proliferation, and activation of macrophages. However, there are some contradictory results. Inhibition of NADPH oxidase in experimental studies has shown promising results for both normal tissue protection and tumor sensitization to ionizing radiation. Conclusion: In this article, we aimed to review the role of different subfamilies of NADPH oxidase in radiation-induced early and late normal tissue toxicities in different organs. © 2019 Bentham Science Publishers