Effects of cyclosporin A and a non-immunosuppressive analogue, O-acetyl cyclosporin A, upon the growth of parent and multidrug resistant human lung cancer cells in vitro

Abstract

We have studied the ability of cyclosporin A (CsA) and a non-immunosuppressive analogue, O-acetyl cyclosporin A (OACsA, B3-243) to inhibit the growth of human lung cancer cells in vitro. Using continuous drug exposure and the MTT colorimetric assay to determine cell growth we found that CsA produced partial growth inhibition at doses ranging from 0.5 to 3.0 micrograms ml-1 (0.4-2.4 microM). At progressively higher doses, complete growth inhibition and in situ cell lysis were seen. The P-glycoprotein expressing multidrug resistant (MDR) variant H69/LX4 of the small cell line H69/P was less sensitive to cyclosporins than the parent line, but this was not true of the non-P-glycoprotein expressing MDR variants of large cell line COR-L23 or adenocarcinoma line MOR. Sensitivity to OACsA was approximately 2-fold higher than that to CsA in most of the lines although not in the most sensitive line, COR-L88. Even in COR-L88, exposed to CsA or OACsA for 24 h, clonogenic cell survival was reduced only to 50%. There was no reduction in polyamine content of COR-L23 or COR-L88 cells following 48 h of exposure to CsA or OACsA. The effects on cell growth could not be inhibited by the addition of exogenous putrescine, nor could they be enhanced by the addition of alpha-difluoromethylorthinine. It does not appear therefore that inhibition of polyamine synthesis is the basis of the observed growth inhibition.

Development of vincristine resistance and increased sensitivity to cyclosporin A and verapamil in the human U‐937 lymphoma cell line without overexpression of the 170‐KDa P‐glycoprotein

“…Some of the non-pgp-170-mediated MDR cell lines have also been reported to express collateral sensitivity to resistance modifiers (Twentyman et al, 1992) as well as partial reversal of resistance compatible with the behavior of U-937-vcr (Baas et al, 1990). However, non-pgp-170-mediated MDR is generally associated with a high level of cross-resistance to epipodophyllotoxins (Baas et al, 1990), but this was not demonstrable in the U-937-vcr cell line.…”

Stable RNA Interference–Mediated Suppression of Cyclophilin A Diminishes Non–Small-Cell Lung Tumor Growth In vivo

“…CsA is a well-known inhibitor of peptidylprolyl isomerase activity of CypA and has been studied in lung cancer, mainly in the context of chemotherapy regimens via its inhibition of the P-glycoprotein multidrug resistance protein (31)(32)(33). It has been shown to induce apoptosis in cancer cells, such as retinoblastoma and melanoma, but the exact mechanism has not been elucidated (34)(35)(36). CsA has several drawbacks as a therapeutic agent (i.e., through ''off-target'' effects-CsA is a potent immunosuppressant through inhibition of the calcineurin/nuclear factor of activated T-cell pathway in T cells, and by effects on transforming growth factor h-CsA has been shown to cause tumor progression in non-small-cell lung cancer; ref.…”

Cyclophilin function in Cancer; lessons from virus replication

“…Early work using the nonimmunosuppressive analogue of CsA, O-acetyl cyclosporin A showed a two-fold increase in sensitivity of lung cancer cells compared to CsA [174] however, little work has been carried out on O-acetyl cyclosporin A since. Interestingly, NIM811 induced apoptotic cell death in human melanoma cells.…”