Hydrophobic weakly basic drugs, such as doxorubicin and sunitinib, are currently key components of cancer chemotherapy. It has been shown that several of these compounds induce increase in the total lysosomal volume in tumor cells. Moreover, hypoxia, a hallmark of solid tumors in vivo, promotes chemoresistance by sequestering doxorubicin within lysosomes. To enhance efficacy of chemotherapy, various strategies have been proposed, including those aimed at lysosome destabilization. Inhibition of autophagy is widely recognized as a means to reduce chemoresistance. However, it remains unclear whether doxorubicin itself directly influences lysosomal physiology. In the present study, using the human colorectal carcinoma cell line HCT116, we demonstrate that doxorubicin accumulates substantially in lysosomes even under normoxic conditions. Under normoxia, doxorubicin induces a marked increase in the total lysosomal volume, whereas this effect is weaker under hypoxia. Co-treatment with doxorubicin and chloroquine, a well-established lysosomotropic agent, results in the increased lysosomal volume under both normoxic and hypoxic conditions. Notably, under normoxia, doxorubicin activates TFEB (Transcription Factor EB), a master regulator of lysosomal biogenesis, which likely accounts for the observed expansion of the lysosomal compartment. Furthermore, the lysosomes retain their functional degradative activity in the presence of doxorubicin. A similar effect, lysosomal volume expansion and enhanced degradative capacity in response to doxorubicin, was also observed in the human fibrosarcoma cell line HT1080. In summary, this study provides the first evidence that doxorubicin directly modulates lysosomal parameters in the tumor cell lines under varying oxygen concentrations.
Alekhin et al. (Sun,) studied this question.