Quenching thirst with poison? Paradoxical effect of anticancer drugs

Anticancer drugs have been developed with expectations to provide long-term or at least short-term survival benefits for patients with cancer. Unfortunately, drug therapy tends to provoke malignant biological and clinical behaviours of cancer cells relating not only to the evolution of resistance to specific drugs but also to the enhancement of their proliferation and metastasis abilities. Thus, drug therapy is suspected to impair long-term survival in treated patients under certain circumstances. The paradoxical therapeutic effects could be described as 'quenching thirst with poison', where temporary relief is sought regardless of the consequences. Understanding the underlying mechanisms by which tumours react on drug-induced stress to maintain viability is crucial to develop rational targeting approaches which may optimize survival in patients with cancer. In this review, we describe the paradoxical adverse effects of anticancer drugs, in particular how cancer cells complete resistance evolution, enhance proliferation, escape from immune surveillance and metastasize efficiently when encountered with drug therapy. We also describe an integrative therapeutic framework that may diminish such paradoxical effects, consisting of four main strategies: (1) targeting endogenous stress response pathways, (2) targeting new identities of cancer cells, (3) adaptive therapy- exploiting subclonal competition of cancer cells, and (4) targeting tumour microenvironment.