The novel bis-benzylisoquinoline PY35 reverses P-glycoprotein-mediated multidrug resistance

Cao,Zhonglian; Wright,Meredith; Cheng,Jiekai; Huang,Xiaoxing; Liu,Li; Wu,Lixing; Yang,Ping

doi:10.3892/or.2014.3326

The novel bis-benzylisoquinoline PY35 reverses P-glycoprotein-mediated multidrug resistance

Authors:
- Zhonglian Cao
- Meredith Wright
- Jiekai Cheng
- Xiaoxing Huang
- Li Liu
- Lixing Wu
- Ping Yang
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Affiliations: School of Pharmacy, Fudan University, Shanghai 201203, P.R. China, Horizon Biopharm, San Jose, CA 95131, USA, Hangzhou Inspiration Pharmaceutical Development Co., Ltd., Hangzhou, Zhejiang 310030, P.R. China, Center for Pharmacological Evaluation and Research of SIPI, Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, P.R. China
Published online on: July 11, 2014 https://doi.org/10.3892/or.2014.3326
Pages: 1211-1217

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Abstract

Multidrug resistance (MDR) to chemotherapeutic drugs is the main cause of chemotherapy failure in cancer treatment, and it generally results from expression of ATP-dependent efflux pump P-glycoprotein (P-gp). MDR reversal agents typically act by inhibiting the drug efflux activity of P-gp, thereby increasing intracellular drug levels. PY35 is a novel 5-substituted tetrandrine (Tet) derivative (CN Application No. 201210238709.6). The present study was performed to investigate the ability of PY35 to reverse P-gp-mediated MDR and its mechanism in resistant K562/Adriamycin (ADM), MCF-7/ADM cells and their sensitive cell lines K562 and MCF-7. The ability of PY35 to reverse drug resistance was evaluated by MTT assay. The results showed that PY35 can reverse MDR more effectively than the drug prototype‑Tet. The P-gp function was assessed by the Rhodamine 123 (Rho-123; a P-gp substrate) uptake assay with flow cytometry (FCM) and laser scanning confocal microscopes (LSCM); it showed that the MDR cells pumped Rho-123 out the cells, while their sensitive cells scarcely showed efflux. The presence of PY35 efficiently decreased the efflux of the Rho-123, showing that PY35 can reverse P-gp-mediated MDR by increasing the intracellular concentration of Rho-123. The intracellular accumulation of ADM was analyzed by FCM and showed that the coadministration of PY35 and ADM had clearer accumulation than the treatment of Tet and ADM, and was also more evident than treatment with only ADM. The effect of PY35 on the expression of P-gp was assessed by western blotting. The results indicated that PY35 does not inhibit the expression level of the P-gp. This study indicated that PY35 can effectively reverse P-gp-mediated MDR, not by inhibiting the expression of P-gp, but by the coadministration of PY35 and ADM that could increase the intracellular accumulation of drugs. Thus, PY35 may be a potential inhibitor to overcome drug resistance.

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