Metformin pretreatment reduces effect to dacarbazine and suppresses melanoma cell resistance

Abstract

Oxidative stress role on metformin process of dacarbazine (DTIC) inducing resistance of B16F10 melanoma murine cells are investigated. To induce resistance to DTIC, murine melanoma cells were exposed to increasing concentrations of dacarabazine (DTIC‐res group). Metformin was administered before and during the induction of resistance to DTIC (MET‐DTIC). The oxidative stress parameters of the DTIC‐res group showed increased levels of malondialdehyde (MDA), thiol, and reduced nuclear p53, 8‐hydroxy‐2ʹ‐deoxyguanosine (8‐OH‐DG), nuclear factor kappa B (NF‐ĸB), and Nrf2. In presence of metformin in the resistant induction process to DTIC, (MET‐DTIC) cells had increased antioxidant thiols, MDA, nuclear p53, 8‐OH‐DG, Nrf2, and reducing NF‐ĸB, weakening the DTIC‐resistant phenotype. The exclusive administration of metformin (MET group) also induced the cellular resistance to DTIC. The MET group presented high levels of total thiols, MDA, and reduced percentage of nuclear p53. It also presented reduced nuclear 8‐OH‐DG, NF‐ĸB, and Nrf2 when compared with the control. Oxidative stress and the studied biomarkers seem to be part of the alterations evidenced in DTIC‐resistant B16F10 cells. In addition, metformin administration is able to play a dual role according to the experimental protocol, preventing or inducing a DTIC‐resistant phenotype. These findings should help future research with the aim of investigating DTIC resistance in melanoma.

The dual role of Nrf2 in melanoma: a systematic review

“…This effect does not occur in the exclusive treatment with metformin or DTIC, and both of these conditions lead to the chemoresistance. According to findings, sensitive cells pre-treated with metformin and DTIC had an increased level of Nrf2 compared to the low Nrf2 levels of resistant cells [ 52 ]. Moreover, the cytotoxicity of some therapeutics depends on the activation of the Nrf2/NQO1 (NAD(P)H Quinone Dehydrogenase 1) axis.…”

“… Metformin plays a dual role, inhibiting or promoting a DTIC-resistant phenotype in B16-F10 melanoma cells. [ 52 ] Feng et al, 2022 SK-MEL-28 human melanoma cell line GSK3 expression in melanoma cells is enhanced by nobiletin, which is usually low in cutaneous melanoma. GSK3β inhibits the Keap1/Nrf2/HO-1 Signaling Pathway.…”

Nrf2 protein in melanoma progression, as a new means of treatment

“…Sanches et al, found how metformin impacts oxidative stress as well as how it influences dacarbazine (DTIC) resistance in B16-F10 murine melanoma cells (Sanches et al, 2022). They discovered that pre-treating melanoma cells with metformin before and during the induction of DTIC resistance made the cells more responsive to the treatment because metformin synergized with DTIC.…”

“…This result does not occur in the therapy with metformin or DTIC alone, and both of these circumstances lead to chemoresistance. According to the findings, sensitive cells that had been pre-treated with metformin and DTIC exhibited a higher level of Nrf2 in comparison with the low Nrf2 levels found in resistant cells (Sanches et al, 2022). According to the findings of the Rocha study, temozolomide (TMZ) stimulates the activation of Nrf2, which ultimately results in the production of the GCLM and glutathione S-transferase (GST) genes.…”

“…Studies have shown that supplementing primary chemotherapeutic drugs with metformin has a potentially beneficial effect on reducing chemoresistance in a manner that is dependent on Nrf2. Sanches et al, found how metformin impacts oxidative stress as well as how it influences dacarbazine (DTIC) resistance in B16‐F10 murine melanoma cells (Sanches et al, 2022). They discovered that pre‐treating melanoma cells with metformin before and during the induction of DTIC resistance made the cells more responsive to the treatment because metformin synergized with DTIC.…”