Targeting P-glycoprotein expression and cancer cell energy metabolism: combination of metformin and 2-deoxyglucose reverses the multidrug resistance of K562/Dox cells to doxorubicin

Abstract

P-glycoprotein (P-gp) is one of the major obstacles to efficiency of cancer chemotherapy. Here, we investigated whether combination of metformin and 2-deoxyglucose reverses the multidrug resistance (MDR) of K562/Dox cells and tried to elucidate the possible mechanisms. The combination of metformin and 2-deoxyglucose selectively enhanced the cytotoxicity of doxorubicin against K562/Dox cells. Metformin was not a substrate of P-gp but suppressed the elevated level of P-gp in K562/Dox cells. The downregulation of P-gp may be partly attributed to the inhibition of extracellular signal-regulated kinase pathway. The addition of 2-deoxyglucose to metformin initiated a strong metabolic stress in both K562 and K562/Dox cells. Combination of metformin and 2-deoxyglucose inhibited glucose uptake and lactate production in K562 and K562/Dox cells leading to a severe depletion in ATP and a enhanced autophagy. Above all, P-gp substrate selectively aggravated this ATP depletion effect and increased cell apoptosis in K562/Dox cells. In conclusion, metformin decreases P-gp expression in K562/Dox cells via blocking phosphorylation of extracellular signal-regulated kinase. P-gp substrate increases K562/Dox cell apoptosis via aggravating ATP depletion induced by combination of metformin and 2-deoxyglucose. Our observations highlight the importance of combination of metformin and 2-deoxyglucose in reversing multidrug resistance.

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, , ).…”

Resveratrol induces autophagic apoptosis via the lysosomal cathepsin D pathway in human drug‑resistant K562/ADM leukemia cells

“…However, under sustained exposure to cytotoxic agents, autophagic machinery could be recruited to trigger both caspase-dependent and -independent lethal pathways (17,19). In addition, P-glycoprotein serves a significant role in causing multidrug resistance (30). The expression of P-glycoprotein was also examined, but its expression did not change, indicating that it did not participate in the autophagy cell death induced by resveratrol (data not shown).…”

Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562/ADR Cells

“…NFV, VRP, ADR, paclitaxel, colchicine, and imatinib had strong affinities with 4M2T, with molecular docking simulation scores of 7.85, 6.91, 6.52, 6.31, 5.2, and 9.61, respectively. However, metformin and cisplatin, which are non-P-gp substrates, showed weak affinities with 4M2T, with binding ability scores of 2.31 and 4.08, respectively [20]. In addition, VRP and ADR had the same amino acid residue binding site for 4M2T, A/GLN986; NFV and ADR also had the same amino acid residue binding site for 4M2T, A/GLN721 (Fig.…”