A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells.

Abstract

Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS‐209 is a novel quinoline compound, which reverses P‐glycoprotein (P‐gp)‐mediated MDR. We previously reported that MS‐209 reversed in vitro MDR of human SCLC (SBC‐3/ADM and H69/VP) cells expressing P‐gp. In the present study, we determined the therapeutic effect of MS‐209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC‐3/ADM cells expressing P‐gp were highly resistant to etoposide (VP‐16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC‐3 cells lacking P‐gp expression. MS‐209 restored chemosensitivity of SBC‐3/ADM cells to VP‐16, ADM, and VCR in a dose‐dependent manner in vitro. Intravenous injection with SBC‐3 or SBC‐3/ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell‐depleted severe combined immunodeficiency (SCID) mice, though SBC‐3/ ADM cells more rapidly produced metastases than did SBC‐3 cells. Treatment with VP‐16 and ADM reduced metastasis formation by SBC‐3 cells, whereas the same treatment did not affect metastasis by SBC‐3/ADM cells. Although MS‐209 alone had no effect on metastasis by SBC‐3 or SBC‐3/ADM cells, combined use of MS‐209 with VP‐16 or ADM resulted in marked inhibition of metastasis formation by SBC‐3/ADM cells to multiple organs. These findings suggest that MS‐209 reversed the MDR of SBC‐3/ADM cells, but not SBC‐3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS‐209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.