Synergistic anticancer effects of doxorubicin and metformin combination therapy: A systematic review.

INTRODUCTION: Doxorubicin (DOX) a chemotherapy drug often leads to the development of resistance, in cancer cells after prolonged treatment. Recent studies have suggested that using metformin plus doxorubicin could result in synergic effects. This study focuses on exploring the co-treat treatment of doxorubicin and metformin for various cancers. METHOD: Following the PRISMA guidelines we conducted a literature search using different databases such as Embase, Scopus, Web of Sciences, PubMed, Science Direct and Google Scholar until July 2023. We selected search terms based on the objectives of this study. After screening a total of 30 articles were included. RESULTS: The combination of doxorubicin and metformin demonstrated robust anticancer effects, surpassing the outcomes of monotherapy drug treatment. In vitro experiments consistently demonstrated inhibition of cancer cell growth and increased rates of cell death. Animal studies confirmed substantial reductions in tumor growth and improved survival rates, emphasizing the synergistic impact of the combined therapy. The research' discoveries collectively emphasize the capability of the co-treat doxorubicin-metformin as a compelling approach in cancer treatment, highlighting its potential to address medicate resistance and upgrade generally helpful results. CONCLUSION: The findings of this study show that the combined treatment regimen including doxorubicin and metformin has significant promise in fighting cancer. The observed synergistic effects suggest that this combination therapy could be valuable, in a setting. This study highlights the need for clinical research to validate and enhance the application of the doxorubicin metformin regimen.

Static magnetic field reduces cisplatin resistance via increasing apoptosis pathways and genotoxicity in cancer cell lines.

Cisplatin is a chemotherapy drug widely used in cancer treatment. Alongside its clinical benefits, however, it may inflict intolerable toxicity and other adverse effects on healthy tissues. Due to the limitation of administering a high dose of cisplatin as well as cancer drug resistance, it is necessary to utilize new methods optimizing treatment modalities through both higher therapeutic efficacy and reduced administered doses of radiation and drugs. In this study, sensitive (A2780) and resistant (A2780CP) ovarian carcinoma cells underwent treatment with cisplatin + static magnetic field (SMF). First, the levels of genotoxicity after treatment were evaluated by Comet assay. Then, cell cycle analysis and apoptosis assay were conducted by a flow cytometer. Lastly, the expression levels of genes involved in apoptosis and cellular drug uptake were investigated by PCR. After treating different groups of cells for 24, 48, and 96 h, the co-treatment of SMF and cisplatin as a combination managed to increase the amount of DNA damage in both sensitive and resistant cell lines. A considerable increase in mortality of cells was also observed mostly in the form of apoptosis, which was caused by inhibition of the cell cycle. The combination also increased the expression levels of apoptotic genes, namely P53 and P21; however, it did not have much effect on the expression levels of BCL2. Besides, the levels of CTR1 gene expression increased significantly in the groups receiving the aforementioned combination. Our study suggests that the combination of cisplatin + SMF might have clinical potential which needs further investigations through future studies.

Exploring the Synergistic Effect of Sildenafil and Green Tea Polyphenols on Breast Cancer Stem Cell-like Cells and their Parental Cells: A Potential Novel Therapeutic Approach.

BACKGROUND: Many cancer studies have intensely focused on the role of diet, among other factors involved in cancer establishment. The positive effect of green tea polyphenols (GTP) on controlling breast cancer cells has been reported in several studies. Cancer stem cell-like cells (CSC-LCs) possessing self-renewal, metastatic, and drug-resistant capacities are considered prominent therapeutic targets. In many tumors, inducible nitric oxide synthase (iNOS) expression levels are high; however, they have a dual effect on breast cancer pathogenesis. OBJECTIVE: This study aimed to investigate the cytotoxicity of the iNOS agonist (Sildenafil) and antagonist (LNAME), both alone and in combination with GTP, on MDA-MB-231, CD44+/CD24- CSC-LCs, and their parental cells (MCF-7). METHODS: The cell viability assay has been studied using the MTT assay. To analyze drug-drug combinations, CompuSyn and Combenefit software were used. The cytotoxicity mechanism was determined using flow cytometric analysis. RESULTS: L-NAME and GTP showed a synergistic effect on MDA-MB-231 and CSC-LCs. Such an effect was not observed on MCF-7. Sildenafil and GTP, on the other hand, showed synergistic cytotoxicity in all the cells mentioned above. Flow cytometric tests resulted in more than 70% apoptosis in MDA-MB-231 and MCF-7. Also, sub-G1 arrest among MCF-7 cells and a considerable decrease in ROS production by MDA-MB-231 cells following treatment with Sildenafil and GTP were observed. CONCLUSION: Sildenafil, in combination with flavonoids, may be considered a novel strategy for cancer treatment.

Workplace Risk Factors Assessment in North-Azadegan Oil Field Based on Harmful Agents Risk Priority Index (HARPI).

Background: Considering the necessity of health risk management, the present study conducted to provide a comprehensive model for identifying, evaluating, and prioritizing occupational health risks in an oilfield. Methods: We conducted this descriptive-analytical cross-sectional study in 2022 at the North-Azadegan oil field in Iran. The occupational health risk was assessed using the "Harmful Agents Risk Priority Index" (HARPI) method. Results: Among the employees for the office section in all job groups, ergonomic risks due to people's posture while working has the highest risk score and is the most critical risk for implementing corrective actions. In the operational section, for the HSE group, benzene, the production group, Electromagnetic Fields (EMFs), and other groups, undesirable lighting has the highest risk score, and exposure to Toluene, Ethylbenzene, Xylenes (TEX) has the lowest risk score. In this oil field, controlling exposure to benzene, correcting ergonomic conditions, and controlling noise exposure, with scores of 81.3,74.85 and 71.36, have the highest priority, respectively. Sequentially, Toluene, Xylene, and ethylbenzene, with scores of 10.25,11.61, and 11.61, have the lowest control priority. Conclusion: The proposed model can prioritize the workplaces' harmful agents based on the HARPI score due to exposure to chemicals, physical factors, and analysis posture.

The Impact of Cancer-Associated Fibroblasts on Drug Resistance, Stemness, and Epithelial-Mesenchymal Transition in Bladder Cancer: A Comparison between Recurrent and Non-Recurrent Patient-Derived CAFs.

This study comparatively evaluated the possible effects of recurrent and non-recurrent patient-derived Cancer-Associated Fibroblasts (CAFs-R and -NR) on the bladder cancer cell line, EJ138. Both groups of CAFs increased cisplatin resistance and altered cell cycle distribution alongside induced resistance to apoptosis. Later, the scratch assay confirmed the cell migration-inducing effects of CAFs on cells. Nonetheless, only CAFs-R managed to increase sphere-formation and clonogenic levels in EJ138 cells, which were later validated by upregulating pluripotency transcription factors. Besides, CAFs-R also affected the expression levels of some of the EMT markers. Our study suggests that CAFs-R had stronger pro-tumorigenic effects on EJ138 cells.

Resveratrol as an antitumor agent for glioblastoma multiforme: Targeting resistance and promoting apoptotic cell deaths.

Glioblastoma multiforme (GBM) is one of the most aggressive brain and spinal cord tumors. Despite the significant development in application of antitumor drugs, no significant increases have been observed in the survival rates of patients with GBM, as GBM cells acquire resistance to conventional anticancer therapeutic agents. Multiple studies have revealed that PI3K/Akt, MAPK, Nanog, STAT 3, and Wnt signaling pathways are involved in GBM progression and invasion. Besides, biological processes such as anti-apoptosis, autophagy, angiogenesis, and stemness promote GBM malignancy. Resveratrol (RESV) is a non-flavonoid polyphenol with high antitumor activity, the potential of which, regulating signaling pathways involved in cancer malignancy, have been demonstrated by many studies. Herein, we present the potential of RESV in both single and combination therapy- targeting various signaling pathways- which induce apoptotic cell death, re-sensitize cancer cells to radiotherapy, and induce chemo-sensitizing effects to eventually inhibit GBM progression.

Nobiletin in Cancer Therapy; Mechanisms and Therapy Perspectives.

Cancer has remained to be one of the major challenges in medicine and regarded as the second leading cause of death worldwide. Different types of cancer may resist anti-cancer drugs following certain mutations such as those in tumor suppressor genes, exhaustion of the immune system, and overexpression of drug resistance mediators, which increase the required concentration of anticancer drugs so as to overcome drug resistance. Moreover, treatment with a high dose of such drugs is highly associated with severe normal tissue toxicity. Administration of low-toxic agents has long been an intriguing idea to enhance tumor suppression. Naturally occurring agents e.g., herb-derived molecules have shown a dual effect on normal and malignant cells. On the one hand, these agents may induce cell death in malignant cells, while on the other hand reduce normal cell toxicity. Nobiletin, one of the well-known polymethoxyflavones (PMFs), has reportedly shown various beneficial effects on the suppression of cancer and the protection of normal cells against different toxic agents. Our review aims to explain the main mechanisms underlying nobiletin as an inhibitor of cancer. We have reviewed the mechanisms of cancer cell death caused by nobiletin, such as stimulation of reactive oxygen species (ROS), modulation of immune evasion mechanisms, targeting tumor suppressor genes, and modulation of epigenetic modulators, among others; the inhibitory mechanisms of nobiletin affecting tumor resistance properties such as modulation of hypoxia, multidrug resistance, angiogenesis, epithelial-mesenchymal transition (EMT) have been fully investigated. Also, the inhibition of anti-apoptotic and invasive mechanisms induced by nobiletin will later be discussed. In the end, protective mechanisms of nobiletin on normal cells/tissue, clinical trial results, and future perspectives are reviewed.

Involvement of Nrf2 signaling in lead-induced toxicity.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is used as one of the main protective factors against various pathological processes, as it regulates cells resistant to oxidation. Several studies have extensively explored the relationship between environmental exposure to heavy metals, particularly lead (Pb), and the development of various human diseases. These metals have been reported to be able to, directly and indirectly, induce the production of reactive oxygen species (ROS) and cause oxidative stress in various organs. Since Nrf2 signaling is important in maintaining redox status, it has a dual role depending on the specific biological context. On the one hand, Nrf2 provides a protective mechanism against metal-induced toxicity; on the other hand, it can induce metal-induced carcinogenesis upon prolonged exposure and activation. Therefore, the aim of this review was to summarize the latest knowledge on the functional interrelation between toxic metals, such as Pb and Nrf2 signaling.

Induction of Cancer Cell Death by Apigenin: A Review on Different Cell Death Pathways.

Induction of cell death and inhibition of cell proliferation in cancer have been set as some of the main goals in anti-tumor therapy. Cancer cell resistance leads to less efficient cancer therapy, and consequently, to higher doses of anticancer drugs, which may eventually increase the risk of serious side effects in normal tissues. Apigenin, a nature-derived and herbal agent, which has shown anticancer properties in several types of cancer, can induce cell death directly and/or amplify the induction of cell death through other anti-tumor modalities. Although the main mechanism of apigenin in order to induce cell death is apoptosis, other cell death pathways, such as autophagic cell death, senescence, anoikis, necroptosis, and ferroptosis, have been reported to be induced by apigenin. It seems that apigenin enhances apoptosis by inducing anticancer immunity and tumor suppressor genes, like p53 and PTEN, and also by inhibiting STAT3 and NF-κB signaling pathways. Furthermore, it may induce autophagic cell death and ferroptosis by inducing endogenous ROS generation. Stimulation of ROS production and tumor suppressor genes, as well as downregulation of drug-resistance mediators, may induce other mechanisms of cell death, such as senescence, anoikis, and necroptosis. It seems that the induction of each type of cell death is highly dependent on the type of cancer. These modulatory actions of apigenin have been shown to enhance anticancer effects by other agents, such as ionizing radiation and chemotherapy drugs. This review explains how cancer cell death may be induced by apigenin at the cellular and molecular levels.

Resveratrol in Cancer Therapy: From Stimulation of Genomic Stability to Adjuvant Cancer Therapy: A Comprehensive Review.

Cancer therapy through anticancer drugs and radiotherapy is associated with several side effects as well as tumor resistance to therapy. The genotoxic effects of chemotherapy and radiotherapy may lead to genomic instability and increased risk of second cancers. Furthermore, some responses in the tumor may induce the exhaustion of antitumor immunity and increase the resistance of cancer cells to therapy. Administration of low-toxicity adjuvants to protect normal tissues and improve therapy efficacy is an intriguing strategy. Several studies have focused on natural-derived agents for improving the antitumor efficiency of radiotherapy, chemotherapy, and novel anticancer drugs such as immunotherapy and targeted cancer therapy. Resveratrol is a naturally occurring substance with intriguing antioxidant, cardioprotective, anti-diabetes, and antitumor properties. Resveratrol has been demonstrated to modulate tumor resistance and mitigate normal tissue toxicity following exposure to various drugs and ionizing radiation. Compelling data suggest that resveratrol may be an appealing adjuvant in combination with various anticancer modalities. Although the natural form of resveratrol has some limitations, such as low absorption in the intestine and low bioavailability, several experiments have demonstrated that using certain carriers, such as nanoparticles, can increase the therapeutic efficacy of resveratrol in preclinical studies. This review highlights various effects of resveratrol that may be useful for cancer therapy. Consequently, we describe how resveratrol can protect normal tissue from genomic instability. In addition, the various mechanisms by which resveratrol exerts its antitumor effects are addressed. Moreover, the outcomes of combination therapy with resveratrol and other anticancer agents are reviewed.

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.

Turmeric for Treatment of Irritable Bowel Syndrome: A Systematic Review of Population-Based Evidence.

Background: Irritable bowel syndrome (IBS) is a highly prevalent disorder of the gut interaction characterized by abdominal discomfort and pain associated with altered bowel habits in the absence of structural abnormalities. In spite of IBS' high prevalence and disease burden across the globe, no explanations have been given as to its underlying pathophysiology. As for the treatment of IBS, there is no specific medication, and the most beneficial treatment is usually supportive therapy. Recent animal and human studies have demonstrated the therapeutic potential of curcumin or turmeric in the treatment of IBS. Methods: We systematically reviewed all available evidence supporting curcumin and turmeric's therapeutic potential in relieving IBS symptoms in the present study. For this purpose, a database search was performed using curcumin, turmeric, and IBS and all their equivalents as of the search terms in Web of Science, Pub-Med, Scopus, Ovid, Embase, and Google Scholar from1990 up to Feb 2021. The investigation was then limited to clinical trials, and then nine articles were collected for data analysis. Results: The findings of the included literature showed that curcumin and turmeric alone or in combination with other medications could improve the severity of IBS as well as the quality of life among people who suffer from IBS symptoms. Conclusion: Overall, medications containing curcumin and turmeric extract due to these compounds' anti-inflammatory effects may improve IBS symptoms, particularly abdominal pain and life quality.

Study of lead-induced neurotoxicity in cholinergic cells differentiated from bone marrow-derived mesenchymal stem cells.

The developing brain is susceptible to the neurotoxic effects of lead. Exposure to lead has main effects on the cholinergic system and causes reduction of cholinergic neuron function during brain development. Disruption of the cholinergic system by chemicals, which play important roles during brain development, causes of neurodevelopmental toxicity. Differentiation of stem cells to neural cells is recently considered a promising tool for neurodevelopmental toxicity studies. This study evaluated the toxicity of lead acetate exposure during the differentiation of bone marrow-derived mesenchyme stem cells (bone marrow stem cells, BMSCs) to CCholinergic neurons. Following institutional animal care review board approval, BMSCs were obtained from adult rats. The differentiating protocol included two stages that were pre-induction with ß-mercaptoethanol (BME) for 24 h and differentiation to cholinergic neurons with nerve growth factor (NGF) over 5 days. The cells were exposed to different lead acetate concentrations (0.1-100 µm) during three stages, including undifferentiated, pre-induction, and neuronal differentiation stages; cell viability was measured by MTT assay. Lead exposure (0.01-100 µg/ml) had no cytotoxic effect on BMSCs but could significantly reduce cell viability at 50 and 100 µm concentrations during pre-induction and neuronal differentiation stages. MAP2 and choline acetyltransferase (ChAT) protein expression were investigated by immunocytochemistry. Although cells treated with 100 µm lead concentration expressed MAP2 protein in the differentiation stages, they had no neuronal cell morphology. The ChAT expression was negative in cells treated with lead. The present study showed that differentiated neuronal BMSCs are sensitive to lead toxicity during differentiation, and it is suggested that these cells be used to study neurodevelopmental toxicity.

Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis.

INTRODUCTION: Cancer cell resistance to chemotherapy agents is a challenging issue in treating patients with cancer. Findings suggest that a combination of drugs may have synergistic or additive effects. in the present study, we systematically reviewed the combined regimens of metformin with cisplatin in various treating cancers. METHODS: A comprehensive systematic search was performed in PubMed, Scopus, Embase, and other relevant databases with the following keyword "metformin", "cisplatin", "combination", "using all their equivalents and similar terms. Pooled odds ratio (OR) and 95% confidence intervals of cell viability and tumor volume as primary outcomes were calculated using Der-Simonian and Laird method while random effects meta-analysis was used, taking into account clinical and statistical heterogeneity. RESULTS: Overall, 44 studies were retrieved, Findings of the present meta-analysis showed that combined regimens of metformin plus cisplatin was significantly associated with decreased odds of tumor volume and cell viability for all cancers compared with cisplatin alone (pooled OR: 0.40; 95% CI: 0.27, 0.58) and (pooled OR: 0.49; 95% CI: 0.42, 0.58) respectively. The result was same for cell viability in lung cancer (pooled OR: 0.59; 95% CI: 0.49, 0.70). The tumor size reduction and the response rate were evident in the animal xenografts model. CONCLUSION: Findings indicated that combining metformin with cisplatin is a practical therapeutic approach to increase treatment efficacy in the case of cell viability and tumor volume and minimize side effects. A combination of metformin with cisplatin could enhance treatment efficacy through synergistic inhibitory effects on the growth of cancer cells.

Modulation of the immune system by melatonin; implications for cancer therapy.

Immune system interactions within the tumour have a key role in the resistance or sensitization of cancer cells to anti-cancer agents. On the other hand, activation of the immune system in normal tissues following chemotherapy or radiotherapy is associated with acute and late effects such as inflammation and fibrosis. Some immune responses can reduce the efficiency of anti-cancer therapy and also promote normal tissue toxicity. Modulation of immune responses can boost the efficiency of anti-tumour therapy and alleviate normal tissue toxicity. Melatonin is a natural body agent that has shown promising results for modulating tumour response to therapy and also alleviating normal tissue toxicity. This review tries to focus on the immunomodulatory actions of melatonin in both tumour and normal tissues. We will explain how anti-cancer drugs may cause toxicity for normal tissues and how tumours can adapt themselves to ionizing radiation and anti-cancer drugs. Then, cellular and molecular mechanisms of immunoregulatory effects of melatonin alone or combined with other anti-cancer agents will be discussed.

Study of the chlorpyrifos neurotoxicity using neural differentiation of adipose tissue-derived stem cells.

Chlorpyrifos (CPF) is the most commonly used organophosphorus insecticide which causes neurodevelopmental toxicity. So far, animals have been used as ideal models for neurotoxicity studies, but working with animals is very expensive, laborious, and ethically challenging. This has encouraged researchers to seek alternatives. During recent years, several studies have reported successful differentiation of embryonic and adult stem cells to neurons. This has provided an excellent model for neurotoxicologic studies. In this study, neural differentiation of mouse adipose tissue-derived stem cells (ADSCs) was used as an in vitro model for investigation of CPF neurotoxicity. For this purpose, mouse ADSCs were cultured in a medium containing knockout serum replacement and were treated with different concentrations of CPF at several stages of differentiation. Cytotoxic effect of CPF and the expression of neuron-specific genes and proteins were studied in the differentiating ADSCs. Furthermore, the activity of acetylcholinesterase was assessed by Ellman assay at different stages of differentiation. This study showed that up to 500 µM CPF did not alter viability of the undifferentiated ADSCs, whereas viability of the differentiating cells decreased with 500 µM CPF. CPF upregulated the expression of some neuron-specific genes and seemed to decrease the number of ß-tubulin III and MAP2 proteins-expressing cells. There was no detectable acetylcholine esterase activity in differentiated ADSCs. In summary, it was shown that CPF treatment can decrease the viability of ADSC-derived neurons and dysregulate the expression of some neuronal markers through acetylcholinesterase-independent mechanisms. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1510-1519, 2016.