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Arzneimittelforschung 2011; 61(11): 622-630
DOI: 10.1055/s-0031-1300565
Antibiotics · Antimycotics · Antiparasitics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Effects of the multidrug resistance modulator HZ08 on the apoptosis pathway in human chronic leukaemia cell line K562/A02

Juan Cen
1   Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China
,
Yi-Lin Zhu
1   Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China
,
Yu Yang
1   Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China
,
Jun-Rong Zhu
2   Department of Pharmacy, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, P. R. China
,
Wei-Rong Fang
1   Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China
,
Wen-Long Huang
3   Center of Drug Discovery, China Pharmaceutical University, Nanjing, P. R. China
,
Yun-Man Li
1   Department of Physiology, China Pharmaceutical University, Nanjing, P. R. China
,
Yi-Fu Tao
2   Department of Pharmacy, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, P. R. China
› Author Affiliations
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Publication History

Publication Date:
06 February 2012 (online)

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Abstract

Cancer fails to respond to chemotherapy by acquiring multidrug resistance in over 90% of patients. A previous study revealed that multidrug resistance modulator HZ08 had great multidrug resistance reversal effect in vitro and in vivo. It could enhance adriamycin (doxorubicin) induced intrinsic apoptosis pathway and rectify cell cycle and some apoptosis related proteins in human breast resistant cancer MCF-7/ADM cells. This study detected Rh l23 accumulation to assess the effect of HZ08 on P-glycoprotein function in human chronic leukaemia cell line K562/A02. Moreover, mitochondria membrane potential, cytochrome c release and caspase-3 activity were analyzed for HZ08 treatment with or without vincristine. Since pretreatment with HZ08 could also reverse the multidrug resistance to vincristine in K562/A02 cells, the individual influence of HZ08 was further detected on apoptotic regulator like Bcl-2, Bax, p53, cell cycle checkpoints and proliferation regulatory factors like survivin, hTERT, c-Myc, c-Fos, c-Jun. Finally, it revealed that HZ08 increased vincristine induced activation in intrinsic apoptosis pathway by inhibition of P-gp mediated efflux. In addition, the outstanding reversal effect of HZ08 should also attribute to its individual effect on apoptosis and proliferation related regulatory factors. It renders HZ08 possibility of application in pretreatment to reverse multidrug resistance while avoiding unexpected drug interactions and accumulative toxicity.

Key words

Apoptosis - Cancer - Human telomerase reverse transcriptase - HZ08 - K562/A02 cells - Multidrug resistance
 

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