Cancer side population (SP) cells with cancer stem cell-like properties are thought to be responsible for
lung cancer chemotherapy resistance and currently no
drug can efficiently target them.
Breast cancer resistance
protein (BRCP/ABCG2) is a major
drug transporter in protecting
lung cancer SP cells from
cytotoxic agents. We showed that a low concentration of
ethanol, which inhibits many
membrane proteins, inhibits ABCG2 in
lung cancer SP cells. Furthermore, cytotoxic
cisplatin (DDP) in 5% (vol/vol)
ethanol kills SP plus non-SP
cancer cells better than either treatment alone in eradicating chemoresistant lung
tumors. We found that 5%
ethanol did not reduce
ABCG2 protein levels, but significantly reduced
ABCG2 protein function by a
Hoechst 33342 extrusion assay, an
ATPase activity assay, and transmission electron microscopy. Further, DDP in 5%
ethanol (5%
ethanol-DDP) induced apoptosis of the SP plus non-SP
cancer cells both in vitro and in vivo. In DDP-resistant A549/DDP lung
tumor-bearing Balb/C nude mice, intratumoral injection of 5%
ethanol-DDP regressed
tumors and significantly improved survivals compared with 5%
ethanol, DDP alone, or control. Intratumoral injection of 5%
ethanol-DDP helped eradicate
tumors in 30% (3/10) of the mice after 4 weeks treatment. By killing SP and non-SP
cancer cells, 5%
ethanol-DDP could eradicate DDP-resistant lung
tumor and extend survival, providing a novel way to improve chemoresistant
lung cancer survival for clinic.