A unique P-glycoprotein interacting agent displays anticancer activity against hepatocellular carcinoma through inhibition of GRP78 and mTOR pathways

Ting-Chun Kuo, Po-Cheng Chiang, Chia-Chun Yu, Kyoko Nakagawa-Goto, Kenneth F Bastow, Kuo-Hsiung Lee, Jih-Hwa Guh
Biochemical Pharmacology 2011 May 1, 81 (9): 1136-44
P-glycoprotein (P-gp) overexpression has been demonstrated in many malignancies being a predominant mechanism by which cancer cells develop multidrug resistance. Several categories of P-gp inhibitors have been demonstrated to potentiate anticancer effect induced by cancer chemotherapeutic drugs through competitive inhibition of P-gp pumping activity. Few studies show the agent that selectively acts on P-gp and, by itself, causes cell apoptosis while remain P-gp-deficient cells unaffected. KNG-I-322, a desmosdumotin B derivative, displayed a direct interaction with P-gp and demonstrated selective anti-proliferative and apoptotic activities in P-gp overexpressed Hep3B/VIN other than P-gp-deficient Hep3B cells. KNG-I-322 induced an inhibitory effect on the phosphorylation of mTOR(Ser2448), p70S6K(Thr389) and 4E-BP(Thr37/46) in Hep3B/VIN but not Hep3B cells. The inhibition was fully blocked by the knockdown of P-gp using siRNA techniques. Notably, the P-gp inhibitor, verapamil, also directly interacted with P-gp but significantly diminished KNG-I-322-induced anti-proliferative activity. After the mechanism study, the data showed that KNG-I-322 induced a dramatic down-regulation of GRP78 expression, which was significantly inhibited by verapamil and completely diminished by the knockdown of P-gp. The protein profile analysis of detergent resistant membranes showed that upon the stimulation by KNG-I-322, the level of P-gp expression in non-raft fractions was dramatically increased and, concomitantly, the GRP78 expression was significantly decreased. Taken together, the data suggest that KNG-I-322 induces anticancer activity in Hep3B/VIN cells through a direct interaction with P-gp, leading to the inhibition of mTOR pathways and the induction of GRP78 down-regulation. The data support that KNG-I-322 is a selective anticancer agent against P-gp-overexpressed other than P-gp-deficient cancer cells.

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