Schedule-dependent interactions between pemetrexed and vinorelbine in human lung cancer cells

Lung cancer is the leading cause of cancer deaths worldwide.
Despite advances and progresses in surgery, chemotherapy, and
radiotherapy over the last decades, the death rate from lung cancer
has remained largely unchanged, which is mainly due to metastatic
disease and multi drug resistance. Because of the overall poor
prognosis, new treatment strategies for lung cancer patients are
urgently needed. The aim of this study was to investigate the
interactions between pemetrexed and vinorelbine for human
adenocarcinoma via various chemotherapy schedules. Vinorelbine and
pemetrexed caused a strong dose-dependent cytotoxic effect in both
HCC and cisplatin resistant HCC (HCC-res) cells. The IC50 values of
vinorelbine against HCC and HCC-res cells were 10.34±1.12 nM and
9.98±2.12 nM, respectively. The IC50 values of Pemetrexed against
these cells were 110.77±17.28 nM and 118.89±18.77 nM respectively.
The application of different therapy schedules induced a
significant time dependent cell growth inhibition on HCC naïve and
cisplatin resistant cells. The therapy scheme of
cisplatinpemetrexedvinorelbine showed the strongest inhibitory
effect on both HCC and HCC-res cells. The application of different
therapy schedules on HCC and HCC-res cells increased the percentage
of cells undergoing apoptosis, except the application of
vinorelbine alone. In both HCC and HCC-res cells,
cisplatinpemetrexedvinorelbine was found the most effective to
induce apoptosis. The application of different therapy schedules on
HCC and HCC-res cells increased cytoplasma calcium concentration.
Only the application of vinorelbine alone failed to increase
calcium concentration in HCC cells. The most elevated calcium
concentration was found in the cells treated with
cisplatinpemetrexedvinorelbine in both HCC and HCC-res cells As a
conclusion, the sequential application of cisplatin, vinorelbine
and pemetrexed has a synergistic effect in cell growth inhibition,
apoptosis induction, and calcium concentration elevation in HCC and
HCC-res cells. The calcium overload could lead to apoptosis, which
was related to the cell growth inhibitory effect of
chemotherapeutics in lung cancer cells. It might cast a light to
develop chemotherapy schedules for patients, and to overcome
cisplatin resistance in lung cancer.