Abstract 3504: Synergism from combinations of monofunctional platinums with phytochemicals in human ovarian cancer cell lines

Abstract

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

Anticancer Activity of Region B Capsaicin Analogs

“…The vanilloid phytochemical 1 displays potent antineoplastic activity in multiple human cancers ,, and can improve the therapeutic efficacy of chemotherapeutic drugs and radiation therapy when used in combination. − Despite such promising applications, the development of 1 as a clinically useful anticancer drug has been limited by its unpleasant side effects. The administration of 1 causes skin redness, hyperalgesia, nausea, intense tearing in the eyes, conjunctivitis, blepharospasm (sustained, forced, and involuntary closing of the eyelids), vomiting, abdominal pain, stomach cramps, bronchospasm, and burning diarrhea in patients. − Clinical trials exploring the pain-relieving activity of 1 have shown that such side effects have resulted in patients discontinuing use of the drug.…”

“…Apart from its pain-relieving activity, 1 exerts a wide variety of biological and pharmacological activities which may have important applications in the therapy of human diseases. − Published data reveal that 1 and other capsaicinoids display strong antioxidant properties, promote energy metabolism, suppress fat accumulation, combat inflammation, − and suppress the growth and progression of a diverse array of human cancers. The antineoplastic activity of 1 has been observed in leukemia, breast, lung, prostate, brain, gastrointestinal, and gynecological cancers. − In several types of human cancers, capsaicin inhibits tumor invasion and metastasis to distant organs. , Apart from exerting direct growth-inhibitory activity toward human tumors, 1 sensitizes human cancer cells to the growth-suppressive effects of established chemotherapy drugs and radiotherapy. − The multiple pharmacological activities of capsaicinoids have laid the foundation for detailed structure–activity-studies (SAR) focused on the development of potent, long-acting agonists and antagonists of the TRPV1 receptor with improved biological activity. Optical crystallography experiments conducted by Nelson and Dawson in 1923 deciphered the structure of 1 (Figure ).…”

“…23 , 24 Apart from exerting direct growth-inhibitory activity toward human tumors, 1 sensitizes human cancer cells to the growth-suppressive effects of established chemotherapy drugs and radiotherapy. 25 − 31 The multiple pharmacological activities of capsaicinoids have laid the foundation for detailed structure–activity-studies (SAR) focused on the development of potent, long-acting agonists and antagonists of the TRPV1 receptor with improved biological activity. Optical crystallography experiments conducted by Nelson and Dawson in 1923 deciphered the structure of 1 ( 32 ) ( Figure 1 ).…”

The Relationship Between Capsaicin in Chili Pepper and Cancer: A Comprehensive Insight

“…Although capsaicin and its cellular pathways relating the anti-cancer mechanism are not clearly understood, increased intracellular calcium, suppression of mitochondrial respiration, induction of calpain activity, formation of reactive oxygen species (ROS), inhibition of coenzyme Q, multiple mechanisms included inhibition of transcription factors such as nuclear factor-kB, STAT 3 (signal transducer and transcription activator) and p53 (tumor protein 53) are included in the relevant processes (9,(13)(14)(15). While the growth of human cancer cells is suppressed by capsaicin, the apoptic activity of cancer chemotherapy agents is supported by multiple mechanisms (9,13,16,17). The p-glycoprotein efflux transporters are inhibited by capsaicin in KB-C2 human endocervical adenocarcinoma cells, and the sensitization of cells to apoptosis and an increase in vinblastine concentration in the cellular microenvironment occurs as a result of treatment of KB-C2 cells with an antimicrotubule drug in the presence of capsaicin (18).…”

Synthesis of platinum complexes with 2-(5-perfluoroalkyl-1,2,4-oxadiazol-3yl)-pyridine and 2-(3-perfluoroalkyl-1-methyl-1,2,4-triazole-5yl)-pyridine ligands and their in vitro antitumor activity

“…However, the cross resistance and severe side effects of platinum drugs, such as nephrotoxicity, have limited their clinical application. In the past years, successful approaches have been employed to solve these drawbacks, combining platinum-based drugs with some other active pharmacophore so that a synergic action can be obtained [6]. Oxadiazole and triazole have been recently used for complexation of metal such as copper, nickel [7], palladium [8] and platinum [9]; 1,2,4-oxadiazoles have been widely studied for their chemistry [10][11][12], these heterocycles have gained attention for their pharmaceutical properties, and additionally, the presence of the fluorinated moiety opens the way to new fluorine-induced activity with respect to corresponding non-fluorinated systems [13][14][15][16] and application in materials [17][18][19][20][21].…”