Effects of the multidrug resistance modulator HZ08 on the apoptosis pathway in human chronic leukaemia cell line K562/A02.
ōancer falls 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 Rh123 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.
Department of Physiology, China Pharmaceutical University, Nanjing, PR China.
Juan
J
Cen
Yi-Lin
YL
Zhu
Yu
Y
Yang
Jun-Rong
JR
Zhu
Wei-Rong
WR
Fang
Wen-Long
WL
Huang
Yun-Man
YM
Li
Yi-Fu
YF
Tao
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis / Q000235:genetics; D007546:Isoquinolines / Q000494:pharmacology*; D020014:K562 Cells; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123; D015398:Signal Transduction / Q000187:drug effects*; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D051034:Inhibitor of Apoptosis Proteins; D007546:Isoquinolines; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide; D020112:Rhodamine 123; D014750:Vincristine; D045304:Cytochromes c; D053148:Caspase 3