Potentiation of growth inhibition due to vincristine by ascorbic acid in a resistant human non-small cell lung cancer cell line.

A human cell subline (PC-9/VCR) resistant to vincristine was established from non-small cell lung cancer PC-9 cells by incremental exposure of the cells to vincristine. The resistant cells showed phenotypic resistance to vincristine (10-fold), colchicine (6.9-fold) and cisplatin (1.4-fold) but they showed sensitivity to other chemotherapeutic agents including melphalan and etoposide VP-16. The characteristics of the vincristine resistance was partially inhibited (5-7-fold) by co-treatment of PC-9/VCR cells with a nontoxic concentration of L-ascorbic acid (25 micrograms/ml). Co-treatment or 96 h pre-treatment with ascorbic acid resulted in potentiation of the vincristine effect on the resistant, but not on the sensitive, cell line. The growth inhibition due to vincristine treatment after 24 or 96 h growth in ascorbic acid-free medium was decreased in the resistant as well as in the sensitive cell line. In both cell lines, enhanced growth rate has been shown after ascorbic acid treatment. Similarly, cross-resistance of PC-9/VCR cells to colchicine could also be blocked by ascorbic acid. In addition, a nontoxic concentration of verapamil, a known multidrug resistance inhibitor, did not affect the resistant phenotype of PC-9/VCR cells. These findings suggest that an ascorbic acid-sensitive mechanism may be involved in drug resistance per se in the human lung cancer cells, which differs from the classical phosphoglycoprotein-mediated or previously reported non-phosphoglycoprotein-mediated multidrug resistance.