Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

Gralewska, Patrycja; Gajek, Arkadiusz; Marczak, Agnieszka; Rogalska, Aneta

doi:10.3390/ijms221910557

Cited by 13 publications

(10 citation statements)

References 91 publications

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“…Cells were classified as live, apoptotic or necrotic on the basis of their morphological and staining characteristics, and the percentage of specific cellular fractions was determined from the total number of cells. Cells were classified as live (bright blue fluorescence), early apoptotic cells (cells showing intensive blue fluorescence), late apoptotic cells (blue–violet stained cells with concomitant apoptotic morphology), and necrotic cells (red fluorescence) [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Gralewska

Gajek

Rybaczek

et al. 2022

Cells

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Olaparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) that inhibits PARP1/2, leading to replication-induced DNA damage that requires homologous recombination repair. Olaparib is often insufficient to treat BRCA-mutated (BRCAMUT) and BRCA wild-type (BRCAWT) high-grade serous ovarian carcinomas (HGSOCs). We examined the short-term (up to 48 h) efficacy of PARPi treatment on a DNA damage response pathway mediated by ATR and CHK1 kinases in BRCAMUT (PEO-1) and BRCAWT (SKOV-3 and OV-90) cells. The combination of ATRi/CHK1i with PARPi was not more cytotoxic than ATR and CHK1 monotherapy. The combination of olaparib with inhibitors of the ATR/CHK1 pathway generated chromosomal abnormalities, independent on BRCAMUT status of cells and formed of micronuclei (MN). However, the beneficial effect of the PARPi:ATRi combination on MN was seen only in the PEO1 BRCAMUT line. Monotherapy with ATR/CHK1 inhibitors reduced BrdU incorporation due to a slower rate of DNA synthesis, which resulted from elevated levels of replication stress, while simultaneous blockade of PARP and ATR caused beneficial effects only in OV-90 cells. Inhibition of ATR/CHK1 increased the formation of double-strand breaks as measured by increased γH2AX expression at collapsed replication forks, resulting in increased levels of apoptosis. Our findings indicate that ATR and CHK1 inhibitors provoke premature mitotic entry, leading to genomic instability and ultimately cell death.

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Section: Methodsmentioning

confidence: 99%

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Gralewska

Gajek

Rybaczek

et al. 2022

Cells

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“…Studies have found that metformin has weight loss, anti-aging, and anti-cardiovascular effects ( 2 ). In recent years, studies have reported an antitumoral effect of the drug, which has been confirmed in various malignant tumor cells such as liver ( 3 ), ovarian ( 4 ) and lung cancer cells. The present study summarizes knowledge on the anti-tumoral effects of metformin and its mechanism in order to provide evidence for the repurposing of this drug for tumor treatment.…”

Section: Introductionmentioning

confidence: 92%

Metformin: A promising drug for human cancers (Review)

Huang

Zhao

et al. 2022

Oncol Lett

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Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo , and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

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“…In some experiment systems, metformin can interact with TP53 and have protective effects on lung endothelial cells [ 190 ]. Metformin can affect the sensitivity of ovarian cancer cells which are either mut-TP53 or TP53-null to the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib [ 191 ]. Decreased levels of AMPK activation (P-AMPK) were detected in PDAC samples as compared to normal tissues.…”

Section: Possibility Of Treatment Of Pdac With Small Molecule Signal ...mentioning

confidence: 99%

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

McCubrey

Yang

Abrams

et al. 2022

Cells

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Approximately 90% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is the fourth leading cause of cancer death world-wide. Therapies for PDAC are largely ineffective due to the dense desmoplastic tumor microenvironment which prevents chemotherapeutic drugs and small molecule inhibitors from exerting effective anti-cancer effects. In this review, we will discuss the roles of TP53 and miRs on the PDAC tumor microenvironment and how loss of the normal functions of TP53 promote tumor progression. The TP53 gene is mutated in approximately 50% of pancreatic cancers. Often, these TP53 mutations are point mutations which confer additional functions for the TP53 proteins. These are called gain of function (GOF) mutations (mut). Another class of TP53 mutations are deletions which result in loss of the TP53 protein; these are referred to TP53-null mutations. We have organized this review into various components/properties of the PDAC microenvironment and how they may be altered in the presence of mutant TP53 and loss of certain miR expression.

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Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

Cited by 13 publications

References 91 publications

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells

Metformin: A promising drug for human cancers (Review)

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

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