Aims

To apply combinations of monofunctional platinums with selected phytochemicals in human ovarian tumor models towards overcoming platinum resistance.

Recently research has been directed at combinations of platinum drugs with tumor active phytochemicals towards a means of overcoming platinum resistance in ovarian cancer. In this study, two designed monofunctional planaramineplatinum(II) complexes, tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (LH3) and tris(benzimidazole)chloroplatinum(II) chloride (LH4), were investigated for activity against human ovarian A2780, cisplatin-resistant A2780 (A2780cisR) and ZD0473-resistant A2780 (A2780ZD0473R) cancer cell lines, alone and in combination with curcumin, genistein, querceitin, capsaicin and resveratrol.

Methods

LH3 and LH4 were synthesized starting with potassium tetracloroplatinate and phytochemicals were obtained from commercial sources. Cytotoxicity was determined using MTT reduction assay. Cellular levels of glutathione before and after treatment were also determined. Interaction of the designed compounds with pBR322 plasmid DNA and damage to DNA in A2780 and A2780cisR cell lines due to interaction with designed compounds alone and in combination with phytochemicals were also investigated. Proteomic studies involving 2D-gel electrophoresis and mass spectrometry were carried out to identify key proteins associated with drug resistance in A2780 and A2780cisR cell lines.

Results and Discussion

LH3 and LH4 were found to be much more active than cisplatin against the resistant tumour models and greatest synergism in activity was observed when combinations of LH3 and LH4 with the phytochemicals were administered as a bolus. For combinations of LH3 and LH4 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were greater in the resistant A2780cisR cell line than in the parental A2780 cell line.

Proteomic studies confirmed significant changes in expression of a number of proteins in A2780cisR cell line compared to the A2780 parent cell line. Greater activity of LH3 and LH4 than cisplatin against the resistant ovarian cell lines indicates that monofunctional platinums can be novel drug candidates with different cytotoxicity profiles from those of Pt drugs currently in use. The steric properties conveyed by the heterocylic ligands play a significant role in modulating their cytotoxicities and binary combination with tumour active phytochemicals can serve to further enhance drug efficacy.

Conclusion

Monofunctional platinums containing bulky planaramine ligands in combination with tumor active phytochemicals have the potential of overcoming platinum resistance in ovarian cancer cell lines.

Acknowledgment

This research was partly supported by Biomedical Science Research Initiative Grant and Biomedical Science Cancer Research Donation Fund.

Citation Format: Laila Arzuman, Fazlul Huq, Jun Qing Yu, Philip Beale. Synergism from combinations of monofunctional platinums with phytochemicals in human ovarian cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3504. doi:10.1158/1538-7445.AM2015-3504

©2015 American Association for Cancer Research.
2015