Mechanisms of cancer cell killing by metformin: a review on different cell death pathways.

Cancer resistance to anti-tumour agents has been one of the serious challenges in different types of cancer treatment. Usually, an increase in the cell death markers can predict a higher rate of survival among patients diagnosed with cancer. By increasing the regulation of survival genes, cancer cells can display a higher resistance to therapy through the suppression of anti-tumour immunity and inhibition of cell death signalling pathways. Administration of certain adjuvants may be useful in order to increase the therapeutic efficiency of anti-cancer therapy through the stimulation of different cell death pathways. Several studies have demonstrated that metformin, an antidiabetic drug with anti-cancer properties, amplifies cell death mechanisms, especially apoptosis in a broad-spectrum of cancer cells. Stimulation of the immune system by metformin has been shown to play a key role in the induction of cell death. It seems that the induction or suppression of different cell death mechanisms has a pivotal role in either sensitization or resistance of cancer cells to therapy. This review explains the cellular and molecular mechanisms of cell death following anticancer therapy. Then, we discuss the modulatory roles of metformin on different cancer cell death pathways including apoptosis, mitotic catastrophe, senescence, autophagy, ferroptosis and pyroptosis.

Investigating the effectiveness of intraoperative rapid parathyroid hormone assay in parathyroidectomy surgery in patients with secondary hyperparathyroidism.

INTRODUCTION: The use of Rapid Intraoperative parathyroid hormone (Io-PTH) assay during surgery in the management of parathyroid tissue in cases of primary hyperparathyroidism has been proven to be effective, while its utilization in secondary hyperparathyroidism (SHPT) has been rarely reported. In the present study, we aim to demonstrate the application of rapid Io-PTH assay in patients with SHPT following chronic kidney disease undergoing parathyroidectomy surgery. METHOD: In this prospective study, five blood samples were taken from patients undergoing parathyroidectomy and upper thymectomy. Among the samples, two were pre-excision, including prior to the first incision, after exploration, and before parathyroids resection. Two additional samples were taken 10 and 20 min after the excision of the parathyroid glands. Another sample was collected twenty-four hours after the operation. Serum Calcium levels and PTH levels were evaluated and analyzed. RESULTS: We successfully managed SHPT in all 36 patients in our study. The patients included 24 males (66.7%) with a mean age of 49.97 ± 14.92. The mean PTH decreased significantly at 10 min, 20 min, one day, and six months after surgery (P < 0.001). The highest reduction occurred 10 min after removal of the parathyroid glands so the mean PTH compared to time zero was reduced from 1737 to 439, and in 100% of cases, more than 50% reduction was seen in PTH. CONCLUSION: A 60% or more reduction in PTH Rapid at 10 min after parathyroidectomy has an accuracy of 94.4% and a positive predictive value of 100%. Thus, if the PTH level does not decrease by more than 60% at 10 min or more than 80% at 20 min, tissue exploration is continued with the aim of finding the ectopic parathyroid gland.

Immunoregulation by resveratrol; implications for normal tissue protection and tumour suppression.

Immune reactions are involved in both tumour and normal tissue in response to therapy. Elevated secretion of certain chemokines, exosomes and cytokines triggers inflammation, pain, fibrosis and ulceration among other normal tissue side effects. On the other hand, secretion of tumour-promoting molecules suppresses activity of anticancer immune cells and facilitates the proliferation of malignant cells. Novel anticancer drugs such as immune checkpoint inhibitors (ICIs) boost anticancer immunity via inducing the proliferation of anticancer cells such as natural killer (NK) cells and CD8+ T lymphocytes. Certain chemotherapy drugs and radiotherapy may induce anticancer immunity in the tumour, however, both have severe side effects for normal tissues through stimulation of several immune responses. Thus, administration of natural products with low side effects may be a promising approach to modulate the immune system in both tumour and normal organs. Resveratrol is a well-known phenol with diverse effects on normal tissues and tumours. To date, a large number of experiments have confirmed the potential of resveratrol as an anticancer adjuvant. This review focuses on ensuing stimulation or suppression of immune responses in both tumour and normal tissue after radiotherapy or anticancer drugs. Later on, the immunoregulatory effects of resveratrol in both tumour and normal tissue following exposure to anticancer agents will be discussed.

Apigenin in cancer therapy: Prevention of genomic instability and anticancer mechanisms.

The incidence of cancer has been growing worldwide. Better survival rates following the administration of novel drugs and new combination therapies may concomitantly cause concern regarding the long-term adverse effects of cancer therapy, for example, second primary malignancies. Moreover, overcoming tumour resistance to anticancer agents has been long considered as a critical challenge in cancer research. Some low toxic adjuvants such as herb-derived molecules may be of interest for chemoprevention and overcoming the resistance of malignancies to cancer therapy. Apigenin is a plant-derived molecule with attractive properties for chemoprevention, for instance, promising anti-tumour effects, which may make it a desirable adjuvant to reduce genomic instability and the risks of second malignancies among normal tissues. Moreover, it may improve the efficiency of anticancer modalities. This paper aims to review various effects of apigenin in both normal tissues and malignancies. In addition, we explain how apigenin may have the ability to protect usual cells against the genotoxic repercussions following radiotherapy and chemotherapy. Furthermore, the inhibitory effects of apigenin on tumours will be discussed.

Mechanisms of cancer cell death induction by paclitaxel: an updated review.

Chemoresistance of cancer cells is a major problem in treating cancer. Knowledge of how cancer cells may die or resist cancer drugs is critical to providing certain strategies to overcome tumour resistance to treatment. Paclitaxel is known as a chemotherapy drug that can suppress the proliferation of cancer cells by inducing cell cycle arrest and induction of mitotic catastrophe. However, today, it is well known that paclitaxel can induce multiple kinds of cell death in cancers. Besides the induction of mitotic catastrophe that occurs during mitosis, paclitaxel has been shown to induce the expression of several pro-apoptosis mediators. It also can modulate the activity of anti-apoptosis mediators. However, certain cell-killing mechanisms such as senescence and autophagy can increase resistance to paclitaxel. This review focuses on the mechanisms of cell death, including apoptosis, mitotic catastrophe, senescence, autophagic cell death, pyroptosis, etc., following paclitaxel treatment. In addition, mechanisms of resistance to cell death due to exposure to paclitaxel and the use of combinations to overcome drug resistance will be discussed.

Nobiletin as an inducer of programmed cell death in cancer: a review.

Cancer resistance to therapy is a big issue in cancer therapy. Tumours may develop some mechanisms to reduce the induction of cell death, thus stimulating tumour growth. Cancer cells may show a low expression and activity of tumour suppressor genes and a low response to anti-tumour immunity. These mutations can increase the resistance of cancer cells to programmed cell death mechanisms such as apoptosis, ferroptosis, pyroptosis, autophagic cell death, and some others. The upregulation of some mediators and transcription factors such as Akt, nuclear factor of κB, signal transducer and activator of transcription 3, Bcl-2, and others can inhibit cell death in cancer cells. Using adjuvants to induce the killing of cancer cells is an interesting strategy in cancer therapy. Nobiletin (NOB) is a herbal-derived agent with fascinating anti-cancer properties. It has been shown to induce the generation of endogenous ROS by cancer cells, leading to damage to critical macromolecules and finally cell death. NOB may induce the activity of p53 and pro-apoptosis mediators, and also inhibit the expression and nuclear translocation of anti-apoptosis mediators. In addition, NOB may induce cancer cell killing by modulating other mechanisms that are involved in programmed cell death mechanisms. This review aims to discuss the cellular and molecular mechanisms of the programmed cell death in cancer by NOB via modulating different types of cell death in cancer.

The effect of shear stress on cardiac differentiation of mesenchymal stem cells.

BACKGROUND: Stem cell therapy is developing as a valuable therapeutic trend for heart diseases. Most recent studies are aimed to find the most appropriate types of stem cells for the treatment of myocardial infarction (MI). The animal models have shown that bone marrow-derived mesenchymal stem cells (BMSCs) are a possible, safe, and efficient type of stem cell used in MI. The previous study demonstrated that 5-Azacytidine (5-Aza) could promote cardiac differentiation in stem cells. METHODS: This study used 5-Aza to induce cardiomyocyte differentiation in BMSCs both in static and microfluidic cell culture systems. For this purpose, we investigated the differentiation by using real-time PCR and Immunocytochemistry (ICC) Analysis. RESULTS: Our results showed that 5-Aza could cause to express cardiac markers in BMSCs as indicated by real-time PCR and immunocytochemistry (ICC). However, BMSCs are exposed to both 5-Aza and shear stress, and their synergistic effects could significantly induce cardiac gene expressions in BMSCs. This level of gene expression was observed neither in 5-Aza nor in shear stress groups only. CONCLUSIONS: These results demonstrate that when BMSCs expose to 5-Aza as well as mechanical cues such as shear stress, the cardiac gene expression can be increased dramatically.

Cardiac inflammation and fibrosis following chemo/radiation therapy: mechanisms and therapeutic agents.

The incidence of cardiovascular disorders is one of the most concerns among people who underwent cancer therapy. The heart side effects of cancer therapy may occur during treatment to some years after the end of treatment. Some epidemiological studies confirm that heart diseases are one of the most common reasons for mortality among patients that were received treatment for cancer. Experimental studies and also clinical investigations indicate that inflammatory changes such as pericarditis, myocarditis, and also fibrosis are key mechanisms of cardiac diseases following chemotherapy/radiotherapy. It seems that chronic oxidative stress, massive cell death, and chronic overproduction of pro-inflammatory and pro-fibrosis cytokines are the key mechanisms of cardiovascular diseases following cancer therapy. Furthermore, infiltration of inflammatory cells and upregulation of some enzymes such as NADPH Oxidases are a hallmark of heart diseases after cancer therapy. In the current review, we aim to explain how radiation or chemotherapy can induce inflammatory and fibrosis-related diseases in the heart. We will explain the cellular and molecular mechanisms of cardiac inflammation and fibrosis following chemo/radiation therapy, and then review some adjuvants to reduce the risk of inflammation and fibrosis in the heart.

Targeting of cancer cell death mechanisms by resveratrol: a review.

Cancer cell death is the utmost aim in cancer therapy. Anti-cancer agents can induce apoptosis, mitotic catastrophe, senescence, or autophagy through the production of free radicals and induction of DNA damage. However, cancer cells can acquire some new properties to adapt to anti-cancer agents. An increase in the incidence of apoptosis, mitotic catastrophe, senescence, and necrosis is in favor of overcoming tumor resistance to therapy. Although an increase in the autophagy process may help the survival of cancer cells, some studies indicated that stimulation of autophagy cell death may be useful for cancer therapy. Using some low toxic agents to amplify cancer cell death is interesting for the eradication of clonogenic cancer cells. Resveratrol (a polyphenol agent) may affect various signaling pathways related to cell death. It can induce death signals and also downregulate the expression of anti-apoptotic genes. Resveratrol has also been shown to modulate autophagy and induce mitotic catastrophe and senescence in some cancer cells. This review focuses on the important targets and mechanisms for the modulation of cancer cell death by resveratrol.

Redox interactions-induced cardiac toxicity in cancer therapy.

Cancer patients undergoing radiotherapy, chemotherapy, or targeted cancer therapy are exposed to the risk of several side effects because of the heavy production of ROS by ionizing radiation or some chemotherapy drugs. Damages to DNA, mitochondria, membrane and other organelles within normal tissue cells such as cardiomyocytes and endothelial cells lead to the release of some toxins which are associated with triggering inflammatory cells to release several types of cytokines, chemokines, ROS, and RNS. The release of some molecules following radiotherapy or chemotherapy stimulates reduction/oxidation (redox) reactions. Redox reactions cause remarkable changes in the level of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Excessive production of ROS and RNS or suppression of antioxidant defense enzymes leads to damage to critical macromolecules, which may continue for long times. Increased levels of some cytokines and oxidative injury are hallmarks of heart injury following cancer therapy. Redox reactions may be involved in several heart disorders such as fibrosis, cardiomyopathy, and endothelium injury. In the current review, we explain the cellular and molecular mechanisms of redox interactions following radiotherapy, chemotherapy, and targeted cancer therapy. Afterward, we explain the evidence of the involvement of redox reactions in heart diseases.

Nrf2 signaling pathway in cisplatin chemotherapy: Potential involvement in organ protection and chemoresistance.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients.

The current knowledge concerning solid cancer and therapy.

Solid cancers comprise a large number of new cases and deaths from cancer each year globally. There are a number of strategies for addressing tumors raised from solid organs including surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, combinational therapy, and stem cell and extracellular vesicle (EV) therapy. Surgery, radiotherapy, and chemotherapy are the dominant cures, but are not always effective, in which even in a localized tumor there is a possibility of tumor relapse after surgical resection. Over half of the cancer patients will receive radiotherapy as a part of their therapeutic schedule. Radiotherapy can cause an abscopal response for boosting the activity of the immune system outside the local field of radiation, but it may also cause an unwanted bystander effect, predisposing nonradiated cells into carcinogenesis. In the context of immunotherapy, immune checkpoint inhibition is known as the standard-of-care, but the major concern is in regard with cold cancers that show low responses to such therapy. Stem-cell therapy can be used to send prodrugs toward the tumor area; this strategy, however, has its own predicaments, such as unwanted attraction toward the other sites including healthy tissues and its instability. A substitute to such therapy and quite a novel strategy is to use EVs, by virtue of their stability and potential to cross biological barriers and long-term storage of contents. Combination therapy is the current focus. Despite advances in the field, there are still unmet concerns in the area of effective cancer therapy, raising challenges and opportunities for future investigations.

Targets for protection and mitigation of radiation injury.

Protection of normal tissues against toxic effects of ionizing radiation is a critical issue in clinical and environmental radiobiology. 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 upregulation 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.

Recent advances and future directions in anti-tumor activity of cryptotanshinone: A mechanistic review.

In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived-natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well-known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic and neuroprotective. Recently, studies have focused on anti-tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti-tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti-tumor activity of chemotherapeutic agents, and elevating accumulation of anti-tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti-tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.

Versatile role of curcumin and its derivatives in lung cancer therapy.

Lung cancer is a main cause of death all over the world with a high incidence rate. Metastasis into neighboring and distant tissues as well as resistance of cancer cells to chemotherapy demand novel strategies in lung cancer therapy. Curcumin is a naturally occurring nutraceutical compound derived from Curcuma longa (turmeric) that has great pharmacological effects, such as anti-inflammatory, neuroprotective, and antidiabetic. The excellent antitumor activity of curcumin has led to its extensive application in the treatment of various cancers. In the present review, we describe the antitumor activity of curcumin against lung cancer. Curcumin affects different molecular pathways such as vascular endothelial growth factors, nuclear factor-κB (NF-κB), mammalian target of rapamycin, PI3/Akt, microRNAs, and long noncoding RNAs in treatment of lung cancer. Curcumin also can induce autophagy, apoptosis, and cell cycle arrest to reduce the viability and proliferation of lung cancer cells. Notably, curcumin supplementation sensitizes cancer cells to chemotherapy and enhances chemotherapy-mediated apoptosis. Curcumin can elevate the efficacy of radiotherapy in lung cancer therapy by targeting various signaling pathways, such as epidermal growth factor receptor and NF-κB. Curcumin-loaded nanocarriers enhance the bioavailability, cellular uptake, and antitumor activity of curcumin. The aforementioned effects are comprehensively discussed in the current review to further direct studies for applying curcumin in lung cancer therapy.

Flaming the fight against cancer cells: the role of microRNA-93.

There have been attempts to develop novel anti-tumor drugs in cancer therapy. Although satisfying results have been observed at a consequence of application of chemotherapeutic agents, the cancer cells are capable of making resistance into these agents. This has forced scientists into genetic manipulation as genetic alterations are responsible for generation of a high number of cancer cells. MicroRNAs (miRs) are endogenous, short non-coding RNAs that affect target genes at the post-transcriptional level. Increasing evidence reveals the potential role of miRs in regulation of biological processes including angiogenesis, metabolism, cell proliferation, cell division, and cell differentiation. Abnormal expression of miRs is associated with development of a number of pathologic events, particularly cancer. MiR-93 plays a significant role in both physiological and pathological mechanisms. At the present review, we show how this miR dually affects the proliferation and invasion of cancer cells. Besides, we elucidate the oncogenesis or oncosuppressor function of miR-93.

Sensing the scent of death: Modulation of microRNAs by Curcumin in gastrointestinal cancers.

Gastrointestinal (GI) cancers with a high incidence rate and adverse complications are related to severe morbidity and mortality around the world. MicroRNAs (miRs) are potential regulators of cellular events, and their aberrant expression occurs in gastrointestinal (GI) cancers. Increasing evidence demonstrates that plant derived-natural compounds are capable of regulation of miRs in cancer therapy. Curcumin is a naturally occurring nutraceutical compound isolated from curcuma longa and possesses valuable pharmacological activities in which anti-tumor activity is of importance, since in suppressing cancer malignancy, curcumin can target various molecular pathways such as STAT3, PTEN, PI3K/Akt, Wnt, and so on. In the present review, our aim is to shed some light on regulation of miRs by curcumin in GI cancers, and demonstrate how regulation of miRs by curcumin can affect proliferation and metastasis of GI cancers. Noteworthy, curcumin affects down-stream targets such as PTEN, VEGFA, PI3K/Akt and so on that are responsible for growth and migration of GI cancers via regulation of miRs. Affected miRs, and their down-stream targets are discussed in this review in a mechanistic way. Besides, challenges for clinical translation of current studies are described.

TGF-ß in radiotherapy: Mechanisms of tumor resistance and normal tissues injury.

Emerging evidences show that changes in tumor stroma can adapt cancer cells to radiotherapy, thereby leading to a reduction in tumor response to treatment. On the other hand, radiotherapy is associated with severe reactions in normal tissues which limit the amount radiation dose received by tumor. These challenges open a window in radiobiology and radiation oncology to explore mechanisms for improving tumor response and also alleviate side effects of radiotherapy. Transforming growth factor beta (TGF-ß) is a well-known and multitasking cytokine that regulates a wide range of reactions and interactions within tumor and normal tissues. Within tumor microenvironment (TME), TGF-ß is the most potent suppressor of immune system activity against cancer cells. This effect is mediated through stimulation of CD4+ which differentiates to T regulatory cells (Tregs), infiltration of fibroblasts and differentiation into cancer associated fibroblasts (CAFs), and also polarization of macrophages to M2 cells. These changes lead to suppression of cytotoxic CD8 + T lymphocytes (CTLs) and natural killer (NK) cells to kill cancer cells. TGF-ß also plays a key role in the angiogenesis, invasion and DNA damage responses (DDR) in cancer cells. In normal tissues, TGF-ß triggers the expression of a wide range of pro-oxidant and pro-fibrosis genes, leading to fibrosis, genomic instability and some other side effects. These properties of TGF-ß make it a potential target to preserve normal tissues and sensitize tumor via its inhibition. In the current review, we aim to explain the mechanisms of upregulation of TGF-ß and its consequences in both tumor and normal tissues.

Cancer and SOX proteins: New insight into their role in ovarian cancer progression/inhibition.

Transcription factors are potential targets in disease therapy, particularly in cancer. This is due to the fact that transcription factors regulate a variety of cellular events, and their modulation has opened a new window in cancer therapy. Sex-determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are potential transcription factors that are involved in developmental processes such as embryogenesis. It has been reported that abnormal expression of SOX proteins is associated with development of different cancers, particularly ovarian cancer (OC). In the present review, our aim is to provide a mechanistic review of involvement of SOX members in OC. SOX members may suppress and/or promote aggressiveness and proliferation of OC cells. Clinical studies have also confirmed the potential of transcription factors as diagnostic and prognostic factors in OC. Notably, studies have demonstrated the relationship between SOX members and other molecular pathways such as ST6Ga1-I, PI3K, ERK and so on, leading to more complexity. Furthermore, SOX members can be affected by upstream mediators such as microRNAs, long non-coding RNAs, and so on. It is worth mentioning that the expression of each member of SOX proteins is corelated with different stages of OC. Furthermore, their expression determines the response of OC cells to chemotherapy. These topics are discussed in this review to shed some light on role of SOX transcription factors in OC.

Resveratrol targeting tau proteins, amyloid-beta aggregations, and their adverse effects: An updated review.

Resveratrol (Res) is a non-flavonoid compound with pharmacological actions such as antioxidant, antiinflammatory, hepatoprotective, antidiabetes, and antitumor. This plant-derived chemical has a long history usage in treatment of diseases. The excellent therapeutic impacts of Res and its capability in penetration into blood-brain barrier have made it an appropriate candidate in the treatment of neurological disorders (NDs). Tau protein aggregations and amyloid-beta (Aß) deposits are responsible for the induction of NDs. A variety of studies have elucidated the role of these aggregations in NDs and the underlying molecular pathways in their development. In the present review, based on the recently published articles, we describe that how Res administration could inhibit amyloidogenic pathway and stimulate processes such as autophagy to degrade Aß aggregations. Besides, we demonstrate that Res supplementation is beneficial in dephosphorylation of tau proteins and suppressing their aggregations. Then, we discuss molecular pathways and relate them to the treatment of NDs.