Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics

SIMPLE SUMMARY: Drug-resistant cancer cells survive under hostile bombardment of chemotherapeutic agents, causing cancer relapse and death. Shocking to many, chemo-resistant cells reprogram lysosomes, also known as the cellular “suicide bags”, to shield themselves from intrusion of chemotherapeutic agents and gain survival advantages. This review presents an evolutionary arms race through which cancer cells become adept at detecting and confining weak-base chemotherapeutic agents in lysosomes. We hope to facilitate translational pharmaceutical research by highlighting lysosomes as fruitful arenas to overcome chemotherapeutic resistance. ABSTRACT: Despite extensive research, resistance to chemotherapy still poses a major obstacle in clinical oncology. An exciting strategy to circumvent chemoresistance involves the identification and subsequent disruption of cellular processes that are aberrantly altered in oncogenic states. Upon chemotherapeutic challenges, lysosomes are deemed to be essential mediators that enable cellular adaptation to stress conditions. Therefore, lysosomes potentially hold the key to disarming the fundamental mechanisms of chemoresistance. This review explores modes of action of classical chemotherapeutic agents, adaptive response of the lysosomes to cell stress, and presents physiological and pharmacological insights pertaining to drug compartmentalization, sequestration, and extracellular clearance through the lens of lysosomes.