A series of hybrid compounds based on natural products—bile acids and dihydroartemisinin—were prepared by different synthetic methodologies and investigated for their in vitro biological activity against HL‐60 leukemia and HepG2 hepatocellular carcinoma cell lines. Most of these hybrids presented significantly improved antiproliferative activities with respect to dihydroartemisinin and the parent bile acid. The two most potent hybrids of the series exhibited a 10.5‐ and 15.4‐fold increase in cytotoxic activity respect to dihydroartemisinin alone in HL‐60 and HepG2 cells, respectively. Strong evidence that an ursodeoxycholic acid hybrid induced apoptosis was obtained by flow cytometric analysis and western blot analysis.
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women. Hormone receptor-positive breast cancer is usually subjected to hormone therapy, while triple-negative breast cancer is more formidable and poses a therapeutic challenge. Glucose transporters are potential targets for the development of anticancer drugs. In search of anticancer agents whose effect could be enhanced by a GLUT1 inhibitor WZB117, we found that MK-2206, a potent allosteric Akt inhibitor, when combined with WZB117, showed a synergistic effect on growth inhibition and apoptosis induction in breast cancer cells, including ER(+) MCF-7 cells and triple-negative MDA-MB-231 cells. The combination index values at 50% growth inhibition were 0.45 and 0.21, respectively. Mechanism studies revealed that MK-2206 and WZB117 exert a synergistic cytotoxic effect in both MCF-7 and MDA-MB-231 breast cancer cells by inhibiting Akt phosphorylation and inducing DNA damage. The combination may also compromise DNA damage repair and ultimately lead to apoptosis. Our findings suggest that the combination of Akt inhibitors and GLUT1 inhibitors could be a novel strategy to combat breast cancer.
Breast cancer is the most prevalent cancer and the second leading cause of cancer death in women. Cisplatin is a commonly used chemotherapeutic drug for breast cancer treatment. Owing to serious side effects, the combination of cisplatin with other drugs is an effective strategy to simultaneously reduce side effects and increase the anticancer efficacy. GLUT1 is an emerging target for cancer treatment since cancer cells usually consume more glucose, a phenomenon called the Warburg effect. In this study, we found that the combination of cisplatin and a novel GLUT1 inhibitor #43 identified from our previous high-throughput screening exerted a synergistic anticancer effect in MCF-7 and MDA-MB-231 breast cancer cells. Mechanism studies in MCF-7 cells revealed that combination of cisplatin and #43 significantly induced apoptosis, intracellular reactive oxygen species, and loss of mitochondrial membrane potential. Furthermore, #43 enhanced the DNA damaging effect of cisplatin. Akt/mTOR downstream signaling and the ERK signaling pathway usually involved in cell growth and survival were inhibited by the combination treatment. On the other hand, phosphorylation of p38 and JNK, which may be associated with apoptosis, was induced by the combination treatment. Altogether, our data indicate that oxidative stress, DNA damage, the Akt/mTOR and MAPK signaling pathways, and apoptosis may be involved in the synergism of cisplatin and #43 in breast cancer cells.
Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in women. Hormone receptor-positive breast cancer is usually subjected to hormone therapy, while triple-negative breast cancer is more formidable and poses a therapeutic challenge. The PI3K/Akt/mTOR signaling pathway plays a crucial role in cancer cell growth, survival, and metabolism. It has been demonstrated that MK-2206, a potent allosteric Akt inhibitor, is cytotoxic against many cancer cell lines and is currently in clinical development. Cancer cells consume more glucose and rely on glycolysis for energy production even in the presence of abundant oxygen, a phenomenon called the Warburg effect. Therefore, glucose transporters responsible for delivering glucose into cells have become targets for the development of anticancer drugs. In search for anticancer agents whose effect could be enhanced by a GLUT1 inhibitor WZB117, we found that MK-2206, when combined with WZB117, showed a synergistic effect on growth inhibition of breast cancer cells, including ER(+) MCF-7 cells and triple-negative MDA-MB-231 cells. The combination index values at 50% growth inhibition were 0.45 and 0.21, respectively. Western blot analysis of proteins involved in the Akt/mTOR pathway revealed that Akt phosphorylation was markedly suppressed in both cell lines by MK-2206 and WZB117 treatment. Phosphorylation of mTOR and its downstream effectors p70S6K and 4E-BP-1 was also dramatically downregulated in MCF-7 but the effect was not as significant in MDA-MB-231 cells, suggesting that other mechanisms might also contribute to cytotoxicity induced by MK-2206 and WZB117. Further investigation revealed that the combination of MK-2206 and WZB117 induced γ-H2AX, a DNA damage marker, in both cell lines. Results from the comet assay confirmed that MK-2206 and WZB117 induced DNA damage. Protein levels of Rad51 and Ku80, participating in homologous recombination and non-homologous end joining repair respectively, were also decreased in MCF-7 cells, suggesting that MK-2206 and WZB117 may not only cause DNA damage, but also impair DNA repair. Furthermore, MK-2206 or WZB117 alone significantly induced ROS, and the combination of both further increased the ROS level within a short time period. In conclusion, this new finding indicates that MK-2206 and WZB117 may exert a synergistic cytotoxic effect in both ER(+) MCF-7 and triple-negative MDA-MB-231 breast cancer cells via ROS induction, which may in turn cause DNA damage. The combination may also compromise DNA damage repair, and ultimately lead to cell death. This finding may have clinical implications. Citation Format: Yu-Liang Li, Hao-Cheng Weng, Lih-Ching Hsu. The combination of MK-2206 and WZB117 exerts a synergistic cytotoxic effect against breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4922.
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