Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis.
Level 5 - mechanism / opinion, no new human data
In vitro bench study in cancer cell lines without human subjects or animal models
PubMed 23111416 · doi:10.1097/CAD.0b013e32835a36db
What was done
Researchers investigated whether chloroquine (CQ) could overcome resistance to the dual PI3K/mTOR inhibitor PI103 in lung carcinoma cell lines. They analyzed lysosomal alterations by evaluating LAMP-1 expression and cathepsin B maturation, lysosomal membrane permeabilization, and apoptosis. The mechanistic roles of caspases and lysosomal enzymes were tested using the inhibitors zVAD.fmk and CA-074me, respectively.
What was found
The abstract reports no numerical values, effect sizes, or exact statistical metrics. It qualitatively reports that PI103 increased lysosomal volume and function (elevated LAMP-1 and mature cathepsin B), while CQ destabilized lysosomal membranes. Co-treatment triggered lysosomal membrane permeabilization, caspase activation, and apoptosis. Inhibition with zVAD.fmk or CA-074me significantly attenuated the loss of cell viability induced by the combination.
Why it matters
These findings suggest that combining lysosomotropic agents like chloroquine with PI3K/mTOR inhibitors represents a potential mechanism-based approach to bypass drug resistance in lung cancer.
Limits
The study is limited to in vitro cell culture models with no in vivo animal or human clinical data. The abstract does not specify the cell lines evaluated, drug concentrations, or quantitative effect sizes.
Cited by
- supports Chloroquine specifically enriches in lysosomal membranes due to its charge, causing lysosomal membrane damage and releasing toxic lysosomal contents into the cytosol rather than acting solely by inhibiting autophagy.