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Open AccessArticle

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

1
School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia
2
Department of Medical Oncology, Concord Repatriation General Hospital, Concord, NSW 2137, Australia
3
Eman Research Ltd., Canberra, ACT 2609, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7500; https://doi.org/10.3390/ijms21207500
Received: 28 August 2020 / Revised: 27 September 2020 / Accepted: 9 October 2020 / Published: 12 October 2020
(This article belongs to the Special Issue Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 2.0)
In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance. View Full-Text
Keywords: ovarian cancer; drug resistance; apoptosis; proteomics; combination; cytotoxicity; artemisinin; oleanolic acid; platinum drugs; cisplatin ovarian cancer; drug resistance; apoptosis; proteomics; combination; cytotoxicity; artemisinin; oleanolic acid; platinum drugs; cisplatin
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Althurwi, S.I.; Yu, J.Q.; Beale, P.; Huq, F. Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models. Int. J. Mol. Sci. 2020, 21, 7500.

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