Docetaxel enhances the cytotoxicity of cisplatin to gastric cancer cells by modification of intracellular platinum metabolism

Abstract

We have examined the combined anticancer effects of docetaxel (DOC) and cisplatin (CDDP) in vitro using the gastric cancer cell lines MKN-45, MKN-74, and TMK-1. Treatment of the cell lines with 30 µ µ µ µg/ml of DOC for 24 h followed by incubation with 3 or 10 µ µ µ µg/ml of CDDP for 24 h showed a clear synergistic effect. Sequence dependency of the agents was observed in these cell lines: DOC followed by CDDP (DC) showed a stronger antitumor effect than CDDP followed by DOC (CD) in all cell lines. To clarify the mechanism of action of the DC combination, total intracellular platinum (Pt) levels were evaluated after treatment with CDDP alone or combined with DC. ocetaxel (DOC) is derived from needles of the yew tree Taxus baccata as a semi-synthetic compound, and has been shown to be active against several kinds of cancer, including gastric cancer. Clinical studies using DOC alone against gastric cancer provided an efficacy rate of approximately 20%, 1) and the antitumor spectrum of DOC was different from those of conventional anticancer agents such as mitomycin C, doxorubicin, and cisplatin (CDDP). 2, 3) Therefore, it is thought that DOC may be useful as a potent agent in combination chemotherapies with conventional chemotherapy agents.Taxoids such as DOC bind to free tubulin and promote the formation of stable microtubules, inhibiting microtubule depolymerization. Recently, a relationship between bcl-2 phosphorylation, Raf-1 (Ras) signaling, and apoptosis during M phase cell cycle arrest induced by DOC was proposed. 4) A study that examined transcription factor levels found that DOC appeared to induce AP-1 activation, and that resistance to DOC was characterized by increased AP-1 levels. 5) Thus, DOC may possess potent ability to alter cell biology through the modification of transcription factor expression levels. We consider that DOC used in combination with conventional anticancer agents may be of considerable benefit in cancer therapy.While the combination chemotherapy of DOC and CDDP has already been applied to the clinical treatment of several types of cancer, with high efficacy rates and only moderate toxic effects in phase I and II studies, 6-9) the mechanism of action of this therapy remains to be clarified. Elucidation of this mechanism, including investigations into synergistic or additive antitumor effects, biochemical modulation, and the importance of sequence dependency, will assist the further clinical application of such combination chemotherapy.In the present study, we demonstrated the synergistic antitumor activity of the DOC and CDDP combination against three gastric cancer cell lines, MKN-45, MKN-74, and TMK-1. We also clarified the sequence dependency and the optimal timeschedule of the two agents, and analyzed the mechanism of DOC enhancement of CDDP antitumor activity in our cell line models by evaluating the amounts of intracellular platinum (Pt) and its intracellular scavenger, glutathione (GSH). Lastly, we examined the expression dynamics of multidrug resistance-associated protein-1 (...

Changes in intracellular redox status influence multidrug resistance in gastric adenocarcinoma cells

“…These transporters mediate drug efflux from tumor cells and may further cause cross-resistance to multiple drugs with diverse chemical structures and curative efficacies. According to previous studies, MDR is observed in the majority of gastric cancers during treatment and is an significant cause of treatment failure (19,20,21).…”

Anticancer Effects of a New Aminosugar-conjugated Platinum Complex Agent Against Cisplatin-resistant Gastric Cancer

“…Indeed, studies into the acquisition of CDDP resistance by cancer cells, decreased CDDP accumulation, increased CDDP inactivation, whereas abnormalities in apoptotic signaling have proposed several different mechanisms (14,15). Abnormal expression of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of transport proteins, multidrug resistance gene-1 (MDR-1) and multidrug resistanceassociated proteins (MRPs) have been associated with CDDP resistance (16,17). In addition, our previous study showed ABCB1 and CDKN2A gene up-regulation in the CDDPresistant gastric cell line MKN45 (18).…”

2300 A multicenter randomized phase II study of docetaxel vs. docetaxel plus cisplatin vs. docetaxel plus S-1 as second-line chemotherapy in metastatic gastric cancer patients who had progressed after cisplatin plus either S-1 or capecitabine

“…Based on the preclinical synergism between docetaxel and either S-1 or cisplatin [11][12][13][14][15], it was hypothesized that a combination of docetaxel and either S-1 or cisplatin as a secondline treatment might have better efficacy than docetaxel alone, even after the failure of first-line cisplatin plus either S-1 or capecitabine. On the other hand, compared to doc- In contrast, the addition of S-1 to docetaxel showed a better PFS (median, 2.7 months vs. 1.3 months; p=0.034) than docetaxel alone without substantial impairment in the QoL or increasing toxicity except for all grades of nausea.…”

“…Furthermore, docetaxel shows synergistic antitumor activity with fluoropyrimidines, particularly S-1, by modulating the expression of enzymes involved in the 5-FU metabolism, including thymidylate synthase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase [11,12]. Docetaxel has also shown synergistic activity with cisplatin in gastric cancer, which was attributed partially to the suppression of the cisplatininduced multidrug resistance-associated protein-1 by docetaxel [13], resulting in the accumulation of intracellular platinum-glutathione complexes. Given that these molecules modulated by docetaxel are involved in the resistance to fluoropyrimidines and cisplatin in gastric cancer [14,15], the hypothesis in this study was that the co-treatment of docetaxel and either S-1 or cisplatin could increase the antitumor activity compared to docetaxel alone, by at least partially overcoming the resistance to fluoropyrimidines or cisplatin in patients whose tumors progressed during or after fluoropyrimidines-or cisplatin-based first-line therapy.…”