Cancer Letters

Cancer Letters

Volume 259, Issue 2, 8 February 2008, Pages 127-137
Cancer Letters

Mini-review
Bypassing cancer drug resistance by activating multiple death pathways – A proposal from the study of circumventing cancer drug resistance by induction of necroptosis

https://doi.org/10.1016/j.canlet.2007.11.007Get rights and content

Abstract

Cancer drug resistance is a complex, dynamic, and “elusive” system rather than merely a matter of some drug-resistant factors. Current pharmacological approaches aim to restore the efficacy of the standard chemotherapy against drug-resistant cancers via reactivating apoptosis and inhibiting drug transporters, simply because the current available anticancer drugs mostly induce apoptosis and many of them are the substrates/inducers of the drug transporters. However, since there are so many different types of defects in apoptotic pathways as well as numerous drug transporters, which could simultaneously contribute to cancer drug resistance, to succeed in the approach is theoretically possible but practically extremely difficult. To circumvent cancer drug resistance is an alternative choice. Since there are multiple death pathways with molecular mechanisms distinct from each other, we previously proposed that the barriers set up in cancer cells to avoid one pathway were not problems for another. Thus, no matter how dynamic, complex, and “elusive” the resistance occurs along one death pathway (e.g., apoptosis), the resistance would be sequestered within this pathway, and would not affect another death pathway with mechanisms distinct from the former, and vice versa, e.g., apoptotic resistant cancers can be sensitive to an induction of a nonapoptotic death. Indeed, we recently demonstrated that the cancer cells resistant to apoptotic inducers such as anthracycline antibiotics, vinca alkaloids, epipodophylotoxins, were sensitive to necroptotic inducers such as shikonin. Therefore, to bypass cancer drug resistance is principally achievable by simultaneously activating multiple death pathways using combined classes of death inducers (apoptosis, autophagy, necroptosis, etc.). Although each class of death inducers has its own action window and limit in killing cancer cells, a rationalized combination of several classes of death inducers that compliment each other would maximize their efficacy while simultaneously minimizing their weakness. Such “mixed bullets” would probably achieve a good therapeutic efficacy by bypassing cancer drug resistance.

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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