Potential Mechanisms of Melatonin in Osteosarcoma and Bone-Related Neoplasms: Updated Review.

Melatonin (N-acetyl-5-methoxytryptamine) is a secretory product of the pineal gland. A great number of studies have been investigating the functions of this indoleamine in various diseases. Excessive proliferation, reduction in apoptosis, increased angiogenesis, invasion, and metastasis are all processes associated with cancerous tissues. In several cancer types, melatonin is reported to significantly impact these processes. Although bone cancer is relatively rare, it is a serious disease that often becomes metastatic, leading to an unsatisfactory prognosis. In recent decades, significant advances have been made in the therapeutic strategies for bone cancer. Nevertheless, few changes have occurred to patients' outcomes or therapeutic methods. Currently used therapeutic strategies including chemotherapy and radiotherapy often show serious side effects. Moreover, therapeutic options are not sufficient in certain cases, such as metastatic forms of the disease. Therefore, there is a need for a more precise definition of the molecular pathways and cellular functions associated with bone cancer to find novel therapeutic approaches. With such advances, the development of new effective therapies for patients with advanced stage or metastatic forms of the disease will be achieved, resulting in an improved prognosis. This review summarizes what is known about the functions of melatonin in osteosarcoma and Ewing's sarcoma. We explain the underlying mechanisms of action by which melatonin serves as an antitumor agent in bone cancer as well as provide an insight into its synergistic effects with other chemotherapeutic drugs.

Virus, Exosome, and MicroRNA: New Insights into Autophagy.

Autophagy is known as a conserved self-eating mechanism that contributes to cells to degrade different intracellular components (i.e., macromolecular complexes, aggregated proteins, soluble proteins, organelles, and foreign bodies). Autophagy needs formation of a double-membrane structure, which is composed of the sequestered cytoplasmic contents, called autophagosome. There are a variety of internal and external factors involved in initiation and progression of autophagy process. Viruses as external factors are one of the particles that could be associated with different stages of this process. Viruses exert their functions via activation and/or inhibition of a wide range of cellular and molecular targets, which are involved in autophagy process. Besides viruses, a variety of cellular and molecular pathways that are activated and inhibited by several factors (e.g., genetics, epigenetics, and environment factors) are related to beginning and developing of autophagy mechanism. Exosomes and microRNAs have been emerged as novel and effective players anticipated in various stages of autophagy. More knowledge in these pathways and identification of accurate roles of them could help to provide better therapeutic approaches in several diseases such as cancer. We highlighted the roles of viruses, exosomes, and microRNAs in the autophagy processes.

The role of dietary polyphenols in alternating DNA methylation in cancer.

Natural products such as curcumin, quercetin, and resveratrol have been shown to have antitumor effectsand several studies have examined their role in treating cancer, either alone or in combination with other chemotherapeutic drugs. These compounds are capable of affecting different cancer-related mechanisms, such as proliferation, inflammation, invasion, and metastasis. Along with all of the benefits of these agents, affecting epigenetic processes is one of the most important aspects of their impact. Epigenetic modifications can be categorized into three main processes that include DNA methylation, histone modification, and regulation of small non-coding RNAs. Therefore, targeting DNA methylation can be used as a cancer treatment strategy by identifying or developing methylation modulators. Herein, we take a look into the studies investigating the role of natural products (e.g. curcumin, resveratrol, epigallocatechin gallate (EGCG), and quercetin) in alternating the DNA methylation status of various cancer cells. We discuss how these compounds reduce the expression of enzymes mediating the methylation of tumor suppressor genes and thereby, increasing the expression of tumor suppressors while reactivating antitumor signaling pathways.

Melatonin as an adjuvant treatment modality with doxorubicin.

Combination chemotherapy seems to be a beneficial choice for some cancer patients particularly when the drugs target different processes of oncogenesis; patients treated with combination therapies sometimes have a better prognosis than those treated with single drug chemotherapy. However, research has shown that this is not always the case, and this approach may only increase toxicity without having a significant effect in augmenting the antitumor actions of the drugs. Doxorubicin (Dox) is one of the most common chemotherapy drugs used to treat many types of cancer, but it also has serious side effects, such as cardiotoxicity, skin necrosis, testicular toxicity, and nephrotoxicity. Many studies have examined the efficiency of melatonin (MLT) as an anticancer agent. In fact, MLT is an anti-cancer agent that has various functions in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis. Herein, we provide a comprehensive evaluation of the literature concerned with the role of MLT as an adjuvant in Dox-based chemotherapies and discuss how MLT may enhance the antitumor effects of Dox (e.g., by inducing apoptosis and suppressing metastasis) while rescuring other organs from its adverse effects, such as cardio- and nephrotoxicity.

Molecular basis of melatonin protective effects in metastasis: A novel target of melatonin.

Currently, cancer is ranked among the top ten causes of death worldwide. Despite the advances made in the field of cancer treatment, 5-year survival rates of various types of cancer are still low due to the recurrence of the disease and/or metastasis. Dissemination of cancer cells, infiltration into the blood vessels, migration to the targeted organs, extravasation, and colonization are the main steps of metastasis. Various factors and signaling pathways are involved in each of these steps. Melatonin (MLT) is a hormone derived from tryptophan and secreted by the pineal gland. This hormone has shown a variety of anti-tumor effects, including anti-oxidative activities, inhibiting the proliferation of tumor cells, inducing apoptosis, and suppressing metastasis. Due to these extensive effects, several studies have been conducted on the applications of MLT in treating different types of cancer. Herein, we review the mechanisms of MLT's effects on the metastasis inhibition of the most lethal types of cancer including the cancer of lung, breast, stomach, kidney, colon, liver, bladder, and pancreas. We discuss how MLT targets different molecules and signaling pathways in each step of the metastasis, such as angiogenesis, remodeling of the extracellular matrix, migration, and epithelial-to-mesenchymal transition.

Cervical Cancer and Novel Therapeutic and Diagnostic Approaches using Chitosan as a Carrier: A Review.

In our knowledge, using appropriate carriers in the delivery of chemotherapeutic drugs, would result in better targeting and therefore it would increase the effectiveness and decrease the side effects of drugs. Chitosan, a natural polymer derived from chitin, has attracted the attention of pharmaceutical industries recently. New research works show that chitosan can not only be used in drug delivery but it can also have some usages in the prevention and diagnosis of cancer. This means that using chitosan Nanoformulations can be a promising approach for prevention, diagnosis, and specially treatment of cervical cancer, the fourth common cancer among the women of the world. We aim to investigate the related papers to find a novel method and preventing more women from suffering.

Melatonin as an adjuvant treatment modality with doxorubicin.

Combination chemotherapy seems to be a beneficial choice for some cancer patients particularly when the drugs target different processes of oncogenesis; patients treated with combination therapies sometimes have a better prognosis than those treated with single drug chemotherapy. However, research has shown that this is not always the case, and this approach may only increase toxicity without having a significant effect in augmenting the antitumor actions of the drugs. Doxorubicin (Dox) is one of the most common chemotherapy drugs used to treat many types of cancer, but it also has serious side effects, such as cardiotoxicity, skin necrosis, testicular toxicity, and nephrotoxicity. Many studies have examined the efficacy of melatonin (MLT) as an anticancer agent. In fact, MLT is an anti-cancer agent that has various functions in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis. Herein, we provide a comprehensive evaluation of the literature concerned with the role of MLT as an adjuvant in Dox-based chemotherapies and discuss how MLT may enhance the antitumor effects of Dox (e.g., by inducing apoptosis and suppressing metastasis) while rescuring other organs from its adverse effects, such as cardio- and nephrotoxicity.

DNA damage response and repair in the development and treatment of brain tumors.

DNA damage response (DDR) comprising DNA repair and cell-cycle checkpoint pathways, is considered as a protective process that maintains the integrity of the genome. However, this mechanism may not be favorable in the context of cancer. Indeed, studies have shown that DDR and repair mechanisms can be involved in the development of different cancers. Furthermore, they may lead to the failure of therapeutic approaches. Thus, studying these mechanisms can be beneficial in a better understanding of cancer development and developing more efficient treatments. Scopus, Google Scholar, and PubMed databases were used for searching articles published on "DNA damage response and DNA repair in the development and treatment of brain tumors". Herein, we review the literature on DNA damage response and DNA repair mechanisms in the development of brain tumors, such as glioma, glioblastoma, and medulloblastoma. Moreover, we summarize the studies that conducted on the role of targeting components of DNA damage response and DNA repair in treating different types of brain cancers, enhancing the currently available therapeutic approaches, and solving the problems in the field of brain cancer therapy.

Molecular and cellular mechanisms of melatonin in breast cancer.

Breast cancer is considered as one of the most important health problems due to its poor prognosis and high rate of mortality and new diagnosed cases. Annually, a great number of deaths are reported in men and women; this means that despite all the improvements in cancer diagnosis and treatment, still, an intense need for more effective approaches exists. Melatonin is a multivalent compound which has a hand in several cellular and molecular processes and therefore, is an appropriate candidate for treatment of many diseases like cancer. Currently, considerable properties of this agent have oriented the research towards investigating its effects specifically in breast cancer. In this review, we gathered a bunch of evidence in order to give a new sight for breast cancer treatment utilizing melatonin. We expect that in coming years, melatonin will become one of the most common therapeutic drugs with lesser side-effects than other chemotherapeutic drugs.

Molecular Signaling Pathways as Potential Therapeutic Targets in Osteosarcoma.

Among primary bone malignancies, osteosarcoma (OS) is the most common form causing morbidity and mortality in both adults and children. The interesting point about this malignancy is that nearly 10-20% of its newly diagnosed cases have developed metastasis. This adds up to the fact that the survival rate of both metastatic and non-metastatic patients of osteosarcoma has not changed in the past 30 years; therefore, it has been suggested that we need to revise our therapeutic options for OS. In recent years, diverse signaling pathways have drawn the attention of the scientific community since they can be great candidates for treating complicated diseases, such as cancer. In this review, we have tried to explain the pathophysiology of osteosarcoma with the help of different signaling pathways taking part in its initiation/progression and explore how this pathway can be targeted for providing more efficient methods.

The role of polyphenols in overcoming cancer drug resistance: a comprehensive review.

Chemotherapeutic drugs are used to treat advanced stages of cancer or following surgery. However, cancers often develop resistance against drugs, leading to failure of treatment and recurrence of the disease. Polyphenols are a family of organic compounds with more than 10,000 members which have a three-membered flavan ring system in common. These natural compounds are known for their beneficial properties, such as free radical scavenging, decreasing oxidative stress, and modulating inflammation. Herein, we discuss the role of polyphenols (mainly curcumin, resveratrol, and epigallocatechin gallate [EGCG]) in different aspects of cancer drug resistance. Increasing drug uptake by tumor cells, decreasing drug metabolism by enzymes (e.g. cytochromes and glutathione-S-transferases), and reducing drug efflux are some of the mechanisms by which polyphenols increase the sensitivity of cancer cells to chemotherapeutic agents. Polyphenols also affect other targets for overcoming chemoresistance in cancer cells, including cell death (i.e. autophagy and apoptosis), EMT, ROS, DNA repair processes, cancer stem cells, and epigenetics (e.g. miRNAs).

Targeting microRNAs by curcumin: implication for cancer therapy.

In spite of all the investigations in the past 20 years that established a great body of knowledge in cancer therapy, utilizing some elderly methods such as plant compound administration might still be useful. Curcumin is a bioactive polyphenol, which has many anticancer properties but its capability in modulating miRNA expression has opened new doors in the field of cancer-targeted therapy. MiRNAs are a class of small noncoding RNAs that are able to regulate gene expression and signaling. In addition, some other effects of these RNAs such as modulating cell differentiation and regulation of cell cycle have made miRNAs great candidates for personalized cancer treatment. In this review, we try to find some answers to the questions on how curcumin exerts its impacts on cancer hallmarks through miRNAs and whether chemotherapy can be replaced by this beneficial plant compound.

Beta-glucans is a Potential Inhibitor of Ovarian Cancer: Based on Molecular and Biological Aspects.

Ovarian cancer is a lethal type of cancer which is initiated to the ovaries and affects 1 out of every 75 women. Due to the high number of deaths (almost 152,000) related to this cancer, it seems that novel efficient therapeutic methods are required in this field. Beta-glucans are a type of glucose linear polymers which have been proven to have a lot of advantageous activities. Recently, investigations have declared that these polysaccharides have the potential to be used as anti-cancer drugs. These agents are able to affect several mechanisms such as inflammation and apoptosis, and that is how cancers are prone to be affected by them. In this review, we attempt to investigate the role of beta-glucans on ovarian cancer. We hope that this paper would give some novel insights into the field of ovarian cancer treatment.

The Effects of Sterol-Related Signaling Pathways on Glioma.

Gliomas are considered as one of the important brain tumors in adults due to their impact on life quality and cognitive functions. Current methods that are used for treating glioma are not satisfying enough. Understanding cellular and molecular events underlying its pathogenesis and progression may lead to the discovery of novel therapeutic approaches. Sterols are a subtype of steroids and are essential for the physiologic functions of eukaryotic cells. Sterols can be produced by protozoans and microheterotrophs. Moreover, they are found in some natural sources, such as plants, animals, fungi, microalgae, and yeasts. Besides the roles of sterols in physiologic processes, studies have shown that they are involved in pathologic processes, including tumorigenesis and tumor progression. As investigations have revealed, sterol-related signaling pathways are involved in glioma and targeting them may result in new therapeutic options for patients. Thus, we summarized some of the sterol-related signaling pathways in glioma and how they can be associated with other signaling pathways, including EGFR/PI3K/Akt/mTOR, P53, and retinoblastoma protein.

Chitosan as possible inhibitory agents and delivery systems in leukemia.

Leukemia is a lethal cancer in which white blood cells undergo proliferation and immature white blood cells are seen in the bloodstream. Without diagnosis and management in early stages, this type of cancer can be fatal. Changes in protooncogenic genes and microRNA genes are the most important factors involved in development of leukemia. At present, leukemia risk factors are not accurately identified, but some studies have pointed out factors that predispose to leukemia. Studies show that in the absence of genetic risk factors, leukemia can be prevented by reducing the exposure to risk factors of leukemia, including smoking, exposure to benzene compounds and high-dose radioactive or ionizing radiation. One of the most important treatments for leukemia is chemotherapy which has devastating side effects. Chemotherapy and medications used during treatment do not have a specific effect and destroy healthy cells besides leukemia cells. Despite the suppressing effect of chemotherapy against leukemia, patients undergoing chemotherapy have poor quality of life. So today, researchers are focusing on finding more safe and effective natural compounds and treatments for cancer, especially leukemia. Chitosan is a valuable natural compound that is biocompatible and non-toxic to healthy cells. Anticancer, antibacterial, antifungal and antioxidant effects are examples of chitosan biopolymer properties. The US Food and Drug Administration has approved the use of this compound in medical treatments and the pharmaceutical industry. In this article, we take a look at the latest advances in the use of chitosan in the treatment and improvement of leukemia.

Nanocellulose-based Delivery Systems and Cervical Cancer: Review of the Literature.

It has become clear that targeted therapy is one of the best options for decreasing the unpleasant side effects of existing common methods and reducing the number of deaths occurred due to many types of cancer. Biocompatible and non-toxic delivery systems are provided by nanomedicine for aiding targeted therapy in many diseases containing cancer. Cervical cancer (CC) is not only the most common gynecological cancer but also is ranked as the fourth common cancer between both men and women. Chemotherapy, radiotherapy, surgery, and immunotherapy are the approaches, which are being used for treating CC patients. However, more efficacy of these methods can be achieved with the help of nanomedicine and novel delivery systems. Nanocellulose is one of the agents used for designing these systems in order to deliver different drugs to a diversity of cancerous cells. In this review, we aim to investigate the competency of nanocellulose for establishing novel therapeutic methods for cervical cancer. We hope that our results help develop more drug delivery systems for targeted therapy to reduce the side effects and induce the efficacy of anti-cancer drugs.

Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases.

Age is an important risk factor for different diseases. The same mechanisms that promote aging are involved in the development and progression of age-associated diseases. Polyphenols are organic compounds found in fruits and vegetables. Due to their beneficial properties (e.g. antioxidant and anti-inflammatory), polyphenols have been extensively used for treating chronic diseases. To exert their functions, polyphenols target various molecular mechanisms and signaling pathways, such as mTOR, NF-κB, and Wnt/ß-catenin. Wnt signaling is a critical pathway for developmental processes. Besides, dysregulation of this signaling pathway has been observed in various diseases. Several investigations have been conducted on Wnt inhibitors at pre-clinical stages, showing promising results. Herein, we review the studies dealing with the role of polyphenols in targeting the Wnt signaling pathways in aging processes and age-associated diseases, including cancer, diabetes, Alzheimer's disease, osteoporosis, and Parkinson's disease.

Anti-cancer properties of quercetin in osteosarcoma.

Osteosarcoma is a primary bone tumor. Although it is a rare disease in general, it is the most common primary bone tumor among children. Despite the significant advances made in the field of osteosarcoma treatment, the outcomes of this disease are still unfavorable. Besides, there is still no targeted therapy for osteosarcoma that can be used in clinical settings. Quercetin is a member of the phytochemical family which is used for different diseases including cardiovascular diseases, diabetes, and cancer. Its anti-cancer effects are examined in many types of cancer including breast, colon, lung, prostate, and pancreatic cancers and have shown promising results. Herein, the studies dealing with the antitumor roles of quercetin in osteosarcoma are reviewed in this article. We take a look into quercetin's ability to affect proliferation, apoptosis, invasion, and chemo-resistance of the osteosarcoma cells through regulating protein expression and signaling pathways.

Epigenetic roles of PIWI proteins and piRNAs in colorectal cancer.

Small non-coding RNAs (sncRNAs) are a subgroup of non-coding RNAs, with less than 200 nucleotides length and no potential for coding proteins. PiRNAs, a member of sncRNAs, were first discovered more than a decade ago and have attracted researcher's attention because of their gene regulatory function both in the nucleus and in the cytoplasm. Recent investigations have found that the abnormal expression of these sncRNAs is involved in many human diseases, including cancers. Colorectal cancer (CRC), as a common gastrointestinal malignancy, is one of the important causes of cancer-related deaths through the entire world and appears to be a consequence of mutation in the genome and epigenetic alterations. The aim of this review is to realize whether there is a relationship between CRC and piRNAs or not.

DNA damage response and repair in osteosarcoma: Defects, regulation and therapeutic implications.

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents which has the survival rate of 20% in its advanced stages. Osteosarcomas are mostly resistance to our common treatments. DNA damage response (DDR) is a specialized multistep process containing abundant proteins which are necessary for the survival of any cell and organism. DDR machinery detects a diversity of DNA lesions and inhibits the cell cycle progression if these lesions are not repairable. DDR is involved in aging, age-related diseases, and cancer. In recent years, DDR inhibitors have gained the attention of researches due to their potentials in offering novel therapeutic targets and improving the response of many cancers to either chemo- or radio-therapy. In this regard, we tried to gather a great body of evidence about the role of DDR ingredients in osteosarcoma's initiation/progression, prognosis, and treatment.