Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration.

Abstract

This Review delves into the mechanisms behind drug resistance in colorectal cancer (CRC), particularly examining the role of nutrient depletion and its contribution to multidrug resistance (MDR). The study highlights metabolic adaptations of cancer cells as well as metabolic adaptations of cancer cells under low nutrient availability, including shifts in glycolysis and lipid metabolism. It emphasizes the significance of MDR1 and its encoded efflux transporter, P-glycoprotein (P-gp/B1), in mediating drug resistance and how pathways such as HIF1α, AKT, and mTOR influence the expression of P-gp/B1 under limited nutrient availability. Additionally, the Review explores the dual roles of autophagy in drug sensitivity and resistance under nutrient limited conditions. It further investigates the involvement of lysosomes and mitochondria, focusing on their roles in drug sequestration and the challenges posed by lysosomal entrapment facilitated by non-enzymatic processes and ABC transporters like P-gp/B1. Finally, the Review underscores the importance of understanding the interplay between drug sequestration, lysosomal functions, nutrient depletion, and MDR1 gene modulation. It suggests innovative strategies, including structural modifications and nanotechnology, as promising approaches to overcoming drug resistance in cancer therapy.