Alterations in cellular DNA repair capacity play a critical role in the onset, progression, and even response to cancer treatment [1]. Because anti-cancer therapies, including ionizing radiation and chemotherapy, are based on DNA damage, regulating the DNA damage response may lead to tumor susceptibility to treatment or resistance to genotoxic agents. Therefore, targeting DNA repair pathways may be a potential therapeutic approach to cancer treatment [2].

Metformin is the first-line treatment for type 2 diabetes mellitus and the most widely used drug for this disease worldwide. Numerous epidemiologic studies have shown a significant association between the use of metformin in people with type 2 diabetes mellitus and a reduction in the risk of many types of cancer [3, 4]. Metformin, in addition to its protective role in cancer, induces apoptosis and inhibits the proliferation of many cancer cells, tumorigenesis, tumor progression in vivo, metastasis, and angiogenesis [5, 6]. On the other hand, metformin improves the response to chemotherapy and radiotherapy, reduces the anticancer drug resistance in diabetic patients with breast cancer, and increases the sensitivity of cancer cells to drugs [7]. Also, metformin protects the skin against UVB damage by reducing its DNA repair capacity [8].

Curcumin is the main active ingredient of turmeric (Curcuma longa) and has antioxidant, antiseptic, antiseptic, antiseptic effects [9]. Epidemiological studies attribute the reduction in cancer incidence to the curcumin-rich diets [10]. The results of treating cells with curcumin show that it inhibits cell proliferation and induces apoptosis [11]. Also, studies proved the induction of DNA damage and the reduction of the expression of DNA repair genes by curcumin in different cancer cell lines [12]. Although the anticancer effects of curcumin have been confirmed in population-based studies regardless of its molecular pathways, there are inconsistencies in the performance of curcumin in various laboratory studies. Studies indicate its protective role against DNA damage as well as reduced DNA repair capacity, especially in the expression of genes involved in double-strand break (DSB) repair pathways [13].

X-ray cross-complementing (XRCC) and breast cancer (BRCA) genes play a role in various pathways of DNA repair pathways [14, 15]. XRCC1 is involved in the base excision repair (BER) pathway; in addition, XRCC2, XRCC3, BRCA1, and BRCA2 are involved in the homologous recombination (HR) pathway, and XRCC4, XRCC5, XRCC6, and XRCC7 are active in non-homologous end joining (NHEJ). BRCA1 works jointly in NHEJ repair, the nucleotide excision repair (NER), HR pathways [14]; however, BRCA2 has a more specific role in DNA repair [15]. Damaged eukaryotic cells are not repaired, but are removed by apoptosis. Increasing the expression of proapoptoses, especially caspase-3 (CASP3) as a “point of no return”, and/or decreasing anti-apoptotic proteins in the Bcl-2 protein family, such as BCL2L1, can shift the balance in favor of cell death after DNA damage treatment [16]. We have previously observed the dose-dependent cytotoxic effect of metformin and curcumin on AGS gastric cancer cell line. Also, based on Chou-Talalay method, it was found that metformin and curcumin with a ratio of 1:625 in 72 h could have a strong synergistic interaction. Furthermore, the results of our previous study showed that metformin and curcumin could inhibit the EMT mechanisms by impeding cell migration and invasion, as well as colony formation; these changes were significantly higher in combination treatments. Furthermore, the combination of metformin and curcumin significantly and selectively increased the cytotoxic effects of chemotherapy drugs on the cancer cell line compared to the normal cell line [17]. According to these results and as the changes in DNA repair capacity and cell apoptosis potential are affected by EMT changes and cancer progression, changes in the expression of genes involved in these pathways were investigated.

Due to the contradictions in the studies and the lack of reports on the effect of curcumin and metformin combination on DNA repair genes in a gastric cancer cell line, our present study aimed at investigating this area.