Targeting P-glycoprotein function, p53 and energy metabolism: Combination of metformin and 2-deoxyglucose reverses the multidrug resistance of MCF-7/Dox cells to doxorubicin

Abstract

Multidrug resistance(MDR) is a major obstacle to efficiency of breast cancer chemotherapy. We investigated whether combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced cytotoxicity of doxorubicin against MCF-7/Dox cells. Combination of the two drugs resumed p53 function via inhibiting overexpression of murine doubleminute 2(MDM2) and murine doubleminute 4(MDM4) leading to G2/M arrest and apoptosis in MCF-7/Dox cells. Combination of the two drugs had no effect on P-glycoprotein mRNA expression and P-glycoprotein ATPase activity but increased doxorubicin accumulation in MCF-7/Dox cells. The increased doxorubicin accumulation maybe associate with metabolic stress. Combination of metformin and 2-deoxyglucose initiated a strong metabolic stress in MCF-7/Dox cells via inhibiting glucose uptake, lactate, fatty acid, ATP production and protein kinase B(AKT)/ mammalian target of rapamycin(mTOR) pathway. Taken together, combination of metformin and 2-deoxyglucose reverses MDR of MCF-7/Dox cells by recovering p53 function and increasing doxorubicin accumulation. Furthermore, doxorubicin selectively increases MCF-7/Dox apoptosis via aggravating metabolic stress induced by metformin plus 2-deoxyglucose. The mutually reinforcing effect made the combination of metformin and 2DG had a better effect on reversing MDR.

Chloride intracellular channel 1 regulates the antineoplastic effects of metformin in gallbladder cancer cells

“…Recent studies have shown that metformin exerts multiple antitumor effects in vivo and in vitro . However, these antitumor effects as well as the related underlying mechanisms vary among different cancer cells.…”

“…Recent studies have shown that metformin exerts multiple antitumor effects in vivo and in vitro. (24)(25)(26) However, these antitumor effects as well as the related underlying mechanisms vary among different cancer cells. In colorectal cancer, metformin suppresses colonic epithelial proliferation by inhibiting the mTOR pathway via AMPK activation.…”

Targeting P‐glycoprotein and SORCIN: Dihydromyricetin strengthens anti‐proliferative efficiency of adriamycin via MAPK/ERK and Ca2+‐mediated apoptosis pathways in MCF‐7/ADR and K562/ADR

“…All of cell lines were kept in the incubator at 37°C with 5% CO 2 and 95% humidity. Maintenance of cell resistance refers to previous description (Xue et al, , ).…”

Metformin enhances the cytotoxic effect of nilotinib and overcomes nilotinib resistance in chronic myeloid leukemia cells

“…Lately, several studies have reported that metformin not only inhibits cell proliferation in breast, gastric, ovarian, and small cell lung cancers [8][9][10][11] but also potentiates the cytotoxic effect of some TKIs in bladder, colorectal, and non-small cell lung cancer [12][13][14]. In addition, it is also known to reverse multidrug resistance by regulating cancer stem cell population or signaling [15][16][17]. However, the effects of metformin on CML have not been elucidated.…”