BACKGROUND: Breast Cancer (BC) is a serious malignancy among women. However, chemotherapy is an important tool for cancer treatments, but the long-term use of chemotherapy drugs may lead to drug resistance and tumor recurrence. Since Breast Cancer Stem Cells (BCSCs) can be the main factor to induce BC treatment resistance and recurrence, investigation of BCSCs signaling pathways can be an effective modality to enhance cancer treatment efficiency.
OBJECTIVE: In this study, the effect of metformin, SB203580, and takinib alone or in combination with radiotherapy on MCF-7 and MDA-MB-231 breast cancer cell lines was evaluated.
METHODS: MCF-7 and MDA-MB-231 breast cancer cell lines were treated with metformin, SB203580, and takinib for 24 or 48 hours, followed by X-ray exposure. The MTT assay and flow cytometry analysis were performed to assess cell growth inhibition and cellular death, CXCr4 expression, and BCSCs, respectively.
RESULTS: The results showed the combination of takinib/SB203580 with radiotherapy to remarkably reduce the CXCR4 expression and BCSCs levels in the MCF-7 cell line. Also, the concurrent administration of takinib/metformin/radiotherapy significantly reduced BCSCs and CXCR4 metastatic markers in the MDA-MB- 231 cells. Since the MAPK signaling pathway has an important role in inducing drug resistance and cell proliferation, the use of SB203580 as an inhibitor of p38 MAPK can improve breast cancer treatment. Furthermore, metformin and ionizing radiation by suppression of the mTOR signaling pathway can control AMPK activation and cellular proliferation.
CONCLUSIONS: Anti-cancer and cytotoxic effects of metformin can be effective in this strategy. In conclusion, the combination of conventional chemotherapeutic drugs, including SB203580, metformin, and takinib with X-ray exposure can be a new approach to diminish the drug resistance of breast cancer.

BACKGROUND: Over recent years, there has been an increasing focus on the repurposing of existing, well-known medications for new, novel usage. One such drug is metformin, typically utilized in the management of diabetes, which demonstrates a positive relationship between its administration and lower cancer morbidity and mortality. Based on this finding, numerous studies and clinical trials have been conducted to examine the potential usage of metformin as an anticancer agent.
OBJECTIVE: This article aims to summarize metformin\'s anticancer effects through reviewing its literatures and patents, with a focus on its potential to be repurposed for cancer therapy.
METHODS: Various databases were examined using keywords, \'Metformin\' and \'Cancer\'. Research articles were collected through the PubMed database, clinical trials were obtained from the Clinical Trials database, and patents were collected through the Google Patents database.
RESULTS: Metformin shows antineoplastic activity in various models. These anticancer properties appear to synergize with existing chemotherapeutics, which allows a reduction in drug dosage without losing potency while minimizing adverse effects. Numerous patents on metformin have been filed which claim various combination therapies, delivery methods, and uses for cancer therapy, displaying an increasing interest in metformin\'s anticancer potential.
CONCLUSIONS: Preclinical studies, along with early phase clinical trials, have examined the antitumor properties of metformin on a variety of cancers. Metformin\'s anticancer effects are well documented, demonstrating a great promise in improving current cancer therapies. However, there is a significant lack of late phase clinical trials, specifically those involving nondiabetic cancer patients, and therefore further research in this area is required.

Hepatocellular carcinoma (HCC) is among the most common cancers in the world with a low survival rate. Our previous study showed Short chain enoyl-CoA hydratase (ECHS1) could bind to HBsAg (HBs) and that ECHS1\'s localization in mitochondria induced HepG2 cell apoptosis. However, the role of the ECHS1 in energy metabolism and autophagy during hepatocellular carcinoma development remains undefined. We aimed to determine what ECHS1 does to energy metabolism and its effects on HCC progression. We performed CCK-8, EdU assays in hepatocellular carcinoma cell lines (HepG2 and HuH7) with stable ECHS1 knock-down. ATP and NADP+/NADPH levels were measured using an colorimetric assay. Our data demonstrated that ECHS1 silencing inhibited cell proliferation and induced autophagy. ECHS1 knockdown did not increase fatty acid synthesis, but decreased cellular ATP. This resulted in AMP-activated protein kinase (AMPK) activation and induced HCC cell autophagy. Our results showed that silencing ECHS1 to attenuate proliferation and induce autophagy may make it a novel cancer therapy target.

Mitochondrial enzyme expression is reduced in adipose tissue from old mice, yet little is known regarding mechanisms that could be mediating, or interventions that could be used, to reverse these changes. The purpose of this study was to examine the relationship between lipolytic and fatty acid reesterification enzymes, 5\' adenosine monophosphate-activated protein kinase and mitochondrial proteins in adipose tissue from young versus old mice. A second aim was to determine whether metformin treatment could rescue the age-associated decline in adipose tissue mitochondrial proteins. Approximately 22-month-old male C57BL/6 mice were fed a diet with or without 0.5% metformin for 8 weeks. Compared with young mice (~11 wk of age), the protein content/phosphorylation of hormone-sensitive lipase, adipose tissue triglyceride lipase, and phosphoenolpyruvate carboxykinase were reduced in old mice. This was paralleled by increases in the plasma nonesterified fatty acid:glycerol ratio and reductions in adipose tissue 5\' adenosine monophosphate-activated protein kinase activity and select mitochondrial proteins in old mice. There were no differences in these variables when comparing adipose tissue from young and 6-month-old mice. While metformin improved glucose homeostasis, it did not increase 5\' adenosine monophosphate-activated protein kinase phosphorylation or mitochondrial enzymes. Our findings demonstrate a co-ordinated down regulation of lipolytic, reesterification, and mitochondrial enzymes in adipose tissue with aging that is unresponsive to metformin treatment.