HZ08, a great regulator to reverse multidrug resistance via cycle arrest and apoptosis sensitization in MCF-7/ADM.
In early studies, it was demonstrated that R-HZ08, S-HZ08 and the racemate had strong reverse efficacy of multidrug resistance in vitro and in vivo (Yan et al., 2008b). The effect was supposed to have direct interaction with multidrug resistance-associated protein (MRP1) in MCF-7/ADM and P-glycoprotein in K562/A02. According to our latest study, we found HZ08 could enhance chemotherapy induced apoptosis by synergistic action on reactive oxygen species generation, GSH depletion, mitochondrial membrane potential depolarization, cytochrome c release and caspase activation. Moreover, the potential selective effect of HZ08 on resistant cells suggested that HZ08 have specific targets for resistance reversal via apoptosis regulation. Therefore, we traced individual influence of HZ08, not only on apoptosis pathway per se but also on apoptosis related intracellular regulation systems. Then we found HZ08 could increase cells in G(0)/G(1) phase and regulate apoptosis related proteins (Bcl-2, Bax) as well as upstream functional molecules (c-Myc and c-Fos), which are usually abnormal in malignancy and responsible for multidrug resistance in MCF-7/ADM. Thereby, chemotherapy induced apoptosis was promoted. R-HZ08 showed better effect than S-HZ08 or the racemate did in most of targets above. Furthermore, HZ08 did not change the concentration of intracellular Ca(2+) which means it would not have side effect as verapamil does. Considering multidrug resistance is multifactorial, HZ08, especially R-HZ08, which could sensitize apoptosis by multiple improvements of upstream malignant characters, will be a promising drug to enhance the effect of chemotherapy in the treatment of multidrug resistant tumor.
Cen
Juan
J
Department of Physiology, China Pharmaceutical University, Nanjing, PR China.
Qi
Yan
Y
Tao
Yi-fu
YF
Deng
Yan
Y
Fang
Wei-rong
WR
Li
Yun-man
YM
Zhang
Lu-yong
LY
Huang
Wen-long
WL
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D053148:Caspase 3; D045304:Cytochromes c; D004317:Doxorubicin; D007546:Isoquinolines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017382:Reactive Oxygen Species; D014700:Verapamil; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide