NBM-T-BMX-OS01, an Osthole Derivative, Sensitizes Human Lung Cancer A549 Cells to Cisplatin through AMPK-Dependent Inhibition of ERK and Akt Pathway

Abstract

Background: Drug combination therapies using cisplatin and natural products are common practice in the treatment of human lung cancer. Osthole is a natural compound extracted from a number of medicinal plants and has been shown to exert strong anticancer activities with low toxicity. Methods: In the present study, NBM-T-BMX-OS01 (BMX), derived from the semi-synthesis of osthole, was evaluated in cisplatin treated A549 cells to investigate its effect on cisplatin resistance in human lung cancer. The anticancer effect of BMX were measured by cell viablity‚ colony formation‚ TUNEL staining‚ flow cytometry and cell cycle assay. The fluorescence staining was performed to detect intracellular and mitochondrial reactive oxygen species (ROS) generation. Western blot analysis, antagonists pretreatment and small interfering RNA (siRNA) transfection were used to determine the potential mechanism. Results: It was found that, in comparison with single cisplatin treatment, the combination of BMX and cisplatin resulted in greater efficacy in inhibition of proliferation and colony formation, apoptosis induction and cell cycle arrest. The results of fluorescence staining showed that the combination effect of BMX and cisplatin was due to oxidative stress induced by mitochondrial ROS generation. In addition, BMX significantly attenuated the phosphorylation of ERK and Akt, two important pro-survival kinases. In contrast, BMX inhibited the activation of AMPK, and knockdown of AMPK using specific siRNA partially reversed BMX-induced inhibition of ERK and Akt, as well as its synthetic effects on cisplatin induced anticancer activity in A549 cells. Conclusion: Taken together, this study provides that BMX might modulate cisplatin resistance through AMPK-ERK and AMPK-Akt pathways. These results also support the role of BMX as a potential drug candidate for use in combination with cisplatin in the treatment of human lung cancer.

Emodin Increases Expression of Insulin-Like Growth Factor Binding Protein 1 through Activation of MEK/ERK/AMPKα and Interaction of PPARγ and Sp1 in Lung Cancer

“…While limited and inconsistent data showed the activation of MEK/ERK and AMPK kinase signaling in the regulation of PPARγ expression [41, 42], our results suggested the important roles of MEK/ERK and AMPKα activation, which were required to stimulate emodin-induced activation and induction of PPARγ. The involvement of these kinase in not only emodin-induced biological functions, such as cancer cell growth inhibition, but also PPARγ signaling-induced responses have been shown in other studies [8, 38, 39, 43], suggesting the critical role of these two signaling pathways in influencing the effect of emodin. It also indicated the upstream signals of PPARγ in this process.…”

Combination of Osthole and Cisplatin Against Rhabdomyosarcoma TE671 Cells Yielded Additive Pharmacologic Interaction by Means of Isobolographic Analysis

“…Additionally, application of osthole decreased the doses of cisplatin used to achieve the same treatment efficiency and potentially ameliorating some of the CDDP-induced side effects. Combination therapy of osthole (23) or its derivative (24) and CDDP was also reported in other single reports, however usually very limited number of drug concentrations were examined, sometimes only one (23), which does not allow to establish a drug-drug type of pharmacokinetic interaction. In our present detailed study, using several CDDP/osthole combinations we were able to clearly demonstrate an additive interaction in RMS cells.…”

Ablation of ATG4B Suppressed Autophagy and Activated AMPK for Cell Cycle Arrest in Cancer Cells

“…Although AMPK might be activated by several other kinases, such as Ca(2+)/calmodulin-dependent kinase (CAMKK2) [35] and mixed-lineage kinases 3 (MLK3) [36], our findings suggest that AMPK might be a suitable marker for tumor-suppressive effects in cancer cells when ATG4B is targeted. Moreover, AMPK is involved in sensitization of cancer cells to chemotherapeutic drugs [37, 38], implying that combinational treatment with ATG4B inhibitor and chemotherapeutic drugs might provide a potential cancer therapy in the future.…”