Iso-pencillixanthone A from a marine-derived fungus reverses multidrug resistance in cervical cancer cells through down-regulating P-gp and re-activating apoptosis

The occurrence of multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transporters, among which, P-glycoprotein (P-gp) plays one of the most important roles. Iso-pencillixanthone A (iso-PXA) is a compound isolated from the marine-derived fungus . No...

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Veröffentlicht in:RSC advances 2018-01, Vol.8 (72), p.41192-41206
Hauptverfasser: Chen, Li, Li, Xinxin, Cheng, Miaomiao, Wang, Siyuan, Zheng, Qiuhong, Liu, Qinying
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Sprache:eng
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Zusammenfassung:The occurrence of multidrug resistance (MDR) is highly associated with the overexpression of ATP-binding cassette (ABC) transporters, among which, P-glycoprotein (P-gp) plays one of the most important roles. Iso-pencillixanthone A (iso-PXA) is a compound isolated from the marine-derived fungus . No studies on the anti-tumor effect of this compound have been reported, except for a few focusing on its bactericidal properties. In this study, we found iso-PXA could stimulate P-gp ATPase activity and attenuate P-gp expression to increase the intracellular drug concentration in the cervical vincristine (VCR)-resistant cell line HeLa/VCR. Then, it increased ROS generation, depolarized MMP, promoted the release of cytochrome from mitochondria, and further activated caspase-9, caspase-3 and PARP to induce cell apoptosis effectively through the intrinsic pathway. Caspase-8 medicated cleavage of Bid into the truncated form tBid partially initiated the mitochondrial apoptotic events. The elevation of the Bax/Bcl-2 ratio, the accumulation of FBW7 and the degradation of Mcl-1 accelerated the iso-PXA induced apoptotic process. The HeLa/VCR cell xenograft model again confirmed that iso-PXA had much better efficacy than vincristine . Taken together, these findings demonstrated that iso-PXA elicited remarkable anti-tumor and anti-MDR activity through inhibiting P-gp expression and function and re-activating the intrinsic apoptosis pathway and , suggesting it as a potential chemotherapeutic lead compound in the treatment of cervical MDR cancers.
ISSN:2046-2069
2046-2069
DOI:10.1039/c8ra09506j