Mini-reviewBypassing cancer drug resistance by activating multiple death pathways – A proposal from the study of circumventing cancer drug resistance by induction of necroptosis
Section snippets
Cancer drug resistance is complex, dynamic, and “elusive” in nature
Like a cancer that is composed of numerous heterogenous clones genetically and phenotypically [1], a drug-resistant cancer is made of numerous drug-resistant clones with different mechanisms of action. Like the cancer progression that is not caused by a single gene defect but rather contributed by many gene defects [1], the cancer drug resistance is not caused by a single drug-resistant factor but rather contributed by combinations of many drug-resistant factors responsible for cell
Restoring the efficacy of the standard chemotherapy by reactivating apoptosis or inhibiting drug transporters is theoretically possible but practically problematic
The principle of the current pharmacological approaches presumes that the efficacy of the standard chemotherapy against the drug-resistant cancers could be restored via reactivating apoptosis and inhibiting the drug transporters, because the molecular and cellular mechanisms of apoptotic resistance and drug transporters are largely understood. The principle obviously also presumes that different drug-resistant factors are responsible for the drug resistance in different cancers, and each
Induction of necroptosis can circumvent apoptotic and multidrug resistance
We previously proposed that, since there were multiple pathways of cell death whose molecular mechanisms were distinct from each other, the barriers set up in cancer cells to avoid one pathway (e.g., apoptosis) were not problems for another [56]. Thus, no matter how many obstacles would be along apoptotic pathway, and no matter how complex, dynamic, and elusive the apoptotic resistance would be, the resistance would be “sequestered” within apoptosis, and would not affect other death pathways
Simultaneous activation of multiple death pathways would principally bypass cancer drug resistance
Would activating multiple death pathways with molecular mechanisms distinct from each other successfully combat the highly dynamic nature of cancer drug resistance? Purely based on our understanding of current knowledge of cancer drug resistance, this would be an effective way to combat cancer drug resistance. As proposed previously by us [56], since the molecular mechanisms of each death pathway were distinct from each other, no matter how dynamic the resistance occured along a pathway, it
Acknowledgements
This work was supported in part by Cheung Kong Scholars Programme (National Ministry of Education, China, and Li Ka Shing Foundation, Hong Kong), China Natural Sciences Foundation project (30772544), China National Ministry of Health Grant (WKJ2006-2-11), the Bureau for Sciences and Technologies Grant (2005C23007), and the Bureau For Traditional Chinese Medicine Grant 2006Z013A, Zhejiang Province, China (all to X. Hu).
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