Highlights d Metformin plus fasting-induced hypoglycemia synergistically reduces tumor growth d PP2A-GSK3b-MCL-1 axis mediates the synergistic cytotoxicity of the combination d Simultaneous CIP2A inhibition and B56d upregulation dictate combination specificity

Cancer therapies that target epigenetic repressors can mediate their effects by activating retroelements within the human genome. Retroelement transcripts can form double-stranded RNA (dsRNA) that activates the MDA5 pattern recognition receptor 1-6 . This state of viral mimicry leads to loss of cancer cell fitness and stimulates innate and adaptive immune responses 7,8 . However, the clinical efficacy of epigenetic therapies has been limited. To find targets that would synergize with the viral mimicry response, we sought to identify the immunogenic retroelements that are activated by epigenetic therapies. Here we show that intronic and intergenic SINE elements, specifically inverted-repeat Alus, are the major source of drug-induced immunogenic dsRNA. These invertedrepeat Alus are frequently located downstream of 'orphan' CpG islands 9 . In mammals, the ADAR1 enzyme targets and destabilizes inverted repeat Alu dsRNA 10 , which prevents activation of the MDA5 receptor 11 . We found that ADAR1 establishes a negative-feedback loop, restricting the viral mimicry response to epigenetic therapy. Depletion of ADAR1 in patient-derived cancer cells potentiates the efficacy of epigenetic therapy, restraining tumour growth and reducing cancer initiation. Therefore, epigenetic therapies trigger viral mimicry by inducing a subset of inverted-repeats Alus, leading to an ADAR1 dependency. Our findings suggest that combining epigenetic therapies with ADAR1 inhibitors represents a promising strategy for cancer treatment.

Histone methylation plays a key role in the regulation of chromatin structure, and its dynamics regulates important cellular processes. The investigation of the role of alterations in histone methylation in cancer has led to the identification of histone methyltransferases and demethylases as promising novel targets for therapy. Lysine-specific demethylase 1(LSD1, also known as KDM1A) is the first discovered histone lysine demethylase, with the ability to demethylase H3K4me1/2 and H3K9me1/2 at target loci in a context-dependent manner. LSD1 regulates the balance between self-renewal and differentiation of stem cells, and is highly expressed in various cancers, playing an important role in differentiation and self-renewal of tumor cells. In this review, we summarize recent studies about the LSD1, its role in normal and tumor cells, and the potential use of small molecule LSD1 inhibitors in therapy.

The histone demethylase LSD1 is deregulated in several tumors, including leukemias, providing the rationale for the clinical use of LSD1 inhibitors. In acute promyelocytic leukemia (APL), pharmacological doses of retinoic acid (RA) induce differentiation of APL cells, triggering degradation of the PML-RAR oncogene. APL cells are resistant to LSD1 inhibition or knockout, but targeting LSD1 sensitizes them to physiological doses of RA without altering of PML-RAR levels, and extends survival of leukemic mice upon RA treatment. The combination of RA with LSD1 inhibition (or knockout) is also effective in other non-APL, acute myeloid leukemia (AML) cells. Nonenzymatic activities of LSD1 are essential to block differentiation, while RA with targeting of LSD1 releases a differentiation gene expression program, not strictly dependent on changes in histone H3K4 methylation. Integration of proteomic/epigenomic/mutational studies showed that LSD1 inhibitors alter the recruitment of LSD1-containing complexes to chromatin, inhibiting the interaction between LSD1 and the transcription factor GFI1.

Preconditioning of mesenchymal stem cells (MSCs) with melatonin (MT) has shown promising results in animal models of myocardial infarction, renal ischemia and cerebral ischemia. Here, we use this strategy in the liver fibrosis induced by CCl4. There were five groups: normal, CCl4, CCl4 + vehicle, CCl4 + BMMSCs and CCl4 + MT-bone marrow (BM)-derived MSCs (MT-BMMSCs). CCl4 was injected twice weekly for 8 weeks and treatment either with cells or vehicle was performed at the beginning of week 5 with a single dose. BMMSCs were preconditioned with MT for 24 h before injection. MT-BMMSCs had a high ability of homing into the injured liver (P ≤ 0.05 vs. BMMSCs). The CCl4 + MT-BMMSCs group showed higher percentage of glycogen storage but lower percentage of collagen and lipid accumulation (P ≤ 0.05 vs. CCl4 + BMMSCs). The CCl4 + MT-BMMSCs group showed lower expressions of transforming growth factor-β1 (TGF-β1) and Bax and lower content of sera alanine aminotransferase (ALT) but higher expressions of matrix metalloproteinases (MMPs) and Bcl2 compared with the BMMSCs group (P ≤ 0.05). The results showed the better therapeutic outcomes of MT preconditioning by probably improving cell homing and also better maintenance of the balance between matrix degrading and accumulating factors.

Purpose: Poor survival rate of mesenchymal stem cells (MSCs) following their transplantation is one of the major challenges in their therapeutic application. Therefore, it is necessary to augment the viability of the MSCs in order to improve their therapeutic efficacy. Several strategies have been used to overcome this problem. Preconditioning of MSCs with oxidative stresses has gained a lot of attention. Therefore, in the present study, we investigated the effects of simultaneous preconditioning of MSCs with hydrogen peroxide and serum deprivation stresses on their survival and resistance to stressful conditions.Methods: MSCs were isolated from human umbilical cord blood. To perform simultaneous preconditioning, the cells were cultured in DMEM medium containing 1, 2.5 and 5 percent FBS and different concentrations of H2O2 (5, 10, 15, 20, 25, 30, 35, 40, 50, 60, 80 and 100 µM) for 24 hrs. Then, the cells were cultured in recovery culture medium. Finally, one group of the cells was exposed to a lethal concentration of H2O2 (300µM), and the other cells were cultivated in FBS free DMEM medium as the lethal situation. In addition, the percentage of apoptotic cells was analyzed using Caspase 3 assay kit.Results: Simultaneous preconditioning of the MSCs with 15µM H2O2 plus serum deprivation, 2.5% FBS, significantly increased the resistance of the cells to the toxicity induced following their cultivation in FBS free DMEM medium. It exerted the protective effect on the cells after treating with the lethal dose of H2O2 as well.Conclusion: Simultaneous preconditioning of MSCs with oxidative and serum deprivation stresses enhances their survival against harsh conditions, which might increase the viability and stability of the MSCs following their transplantation.

No abstract

No abstract