Promising Anticancer Activity of [Bis(1,8-quinolato)palladium (II)] Alone and in Combination.

Due to similar coordination chemistry of palladium and platinum, a large number of palladium compounds as well have been investigated for their anticancer activity. In the present study, we describe synthesis, characterization, and anticancer activity of palladium complex [Bis(1,8-quinolato)palladium (II)], coded as NH3 against seven different cancer cell lines. NH3 is found to have higher antitumor activity than cisplatin against both parent ovarian A2780 cell line and cisplatin-resistant cell lines. Also, NH3 has the lower IC50 value in HT-29 colorectal cancer cell line. The higher antitumor activity of NH3 is due to the presence of bulky 8-Hydroxyquinoline ligand, thus reducing its reactivity. Proteomic study has identified significantly expressed proteins which have been validated through bioinformatics. NH3 has been found to be less toxic than cisplatin at 2.5 mg/kg and 5 mg/kg dosages on mice models. Binary combinations of NH3 with curcumin and epigallocatechin gallate (EGCG) have demonstrated dose and sequence-dependent synergism in ovarian and colorectal cancer models. All of the preclinical studies indicate promising therapeutic potential of NH3 [Bis(1,8-quinolato)palladium (II)] as an anticancer drug.

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

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.

Dose and Sequence Dependent Synergism from the Combination of Oxaliplatin with Emetine and Patulin Against Colorectal Cancer.

BACKGROUND: Colorectal cancer is the third most commonly diagnosed cancer in the world, causing many deaths every year. Combined chemotherapy has opened a new horizon in treating colorectal cancer. The objective of the present study is to investigate the activity of oxaliplatin in combination with emetine and patulin against colorectal cancer models. METHODS: IC50 values of oxaliplatin, emetine and patulin were determined against human colorectal cancer cell lines (HT-29 and Caco-2) using MTT reduction assay. Synergistic, antagonistic and additive effects from the selected binary combinations were determined as a factor of sequence of administration and added concentrations. Proteomics was carried out to identify the proteins which were accountable for combined drug action applying to the selected drug combination. RESULTS: Oxaliplatin in combination with patulin produced synergism against human colorectal cancer models depending on dose and sequence of drug administration. Bolus administration of oxaliplatin with patulin proved to be the best in terms of synergistic outcome. Altered expressions of nine proteins (ACTG, PROF1, PPIA, PDIA3, COF1, GSTP1, ALDOA, TBA1C and TBB5) were considered for combined drug actions of oxaliplatin with patulin. CONCLUSION: Bolus administration of oxaliplatin with patulin has the potential to be used in the treatment of colorectal cancer, and would warrant further evaluation using suitable animal model.

Synthesis of tris(quinoline)monochloroplatinum(II) Chloride and its Activity Alone and in Combination with Capsaicin and Curcumin in Human Ovarian Cancer Cell Lines.

Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. With the idea that the difference may translate into an altered spectrum of activity, monofunctional planaramineplatinum(II) complex tris(quinoline)monochloro-platinum chloride (coded as LH5) was synthesized and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistnat A2780 (A2780(ZD0473R)) cancer cell lines alone and in combination with the phytochemicals capsaicin (Caps) and curcumin (Cur) as a function of concentration and sequence of administration. Cell viability was quantified using the MTT reduction assay, while combination was used as a quantitative measure of the combined drug action. LH5 is found to be more active than cisplatin (CS) against both resistant cell lines. Combination of LH5 with capsaicin showed synergism in all three cell lines, with the bolus being most synergistic. Lack of association between the levels of platinum accumulation and platinum-DNA with cytotoxicity can be seen to indicate that binding with DNA may not be the main determinant of activity of LH5. Greater activity of LH5 compared to cisplatin, especially against the resistant cell lines, indicates that the compound may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy.

Combination of Genistein and Cisplatin with Two Designed Monofunctional Platinum Agents in Human Ovarian Tumour Models.

A great amount of research effort has been directed at platinum compounds that bind with DNA differently from cisplatin with the idea that the difference may translate into an altered spectrum of activity. Recently research has also been directed at applying combinations of platinum agents with tumour-active phytochemicals with the aim of providing a means of overcoming platinum resistance in ovarian cancer. Herein we report the synthesis of monofunctional platinum tris(3-hydroxypyridine)chloroplatinum(II) chloride (coded as LH1) and tris(imidazole)chloroplatinum(II) chloride (coded as LH2), and their activity alone and in combination with genistein and cisplatin against human ovarian A2780, cisplatin-resistant A2780(cisR) and picoplatin-resistant A2780(ZD0473R) cancer cell lines. Although both LH1 and LH2 were found to be less active than cisplatin against the tumour models, they produced synergistic outcomes in combination with genistein. Both the level of cellular accumulation of Pt and of Pt-DNA binding resulting from the combination were greater in the A2780(cisR) cell line than in the parental A2780 cell line, irrespective of the sequence of administration. Absence of association between activity of LH1 and LH2 and the level of Pt-DNA binding indicates that the cell death induced by LH1 and LH2 may not be limited to the effect of their binding with DNA.

Monofunctional Platinum-containing Pyridine-based Ligand Acts Synergistically in Combination with the Phytochemicals Curcumin and Quercetin in Human Ovarian Tumour Models.

With the idea that platinum compounds that bind with DNA differently than cisplatin may be better-able to overcome platinum resistance in ovarian tumor, the monofunctional platinum complex tris(imidazo(1,2-α)pyridine) chloroplatinum(II) chloride (coded as LH6) has been synthesized and investigated for its activity, alone and in combination with the phytochemicals curcumin and quercetin, against human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines. LH6 is found to be more active than cisplatin against the resistant cell lines and its bolus combinations with curcumin and quercetin are found to produce more pronounced cell kill. Whereas platinum accumulation from cisplatin is found to increase almost linearly with time, that from LH6 reaches a maximum at 4 h and is somewhat lowered at 24 h. It is possible that the presence of bulky hydrophobic imidazo (1,2-α-pyridine) ligand in LH6 facilitates its rapid uptake through the cytoplasmic membrane. Lower platinum accumulation at 24 h than at 4 h for LH6 can be seen to imply that efflux processes may be more dominant as the period of incubation is increased. When platinum-DNA binding levels at 24 h are compared, cisplatin is found to be associated with the higher level in the parent A2780 cell line and LH6 in the resistant A2780(cisR) cell line, in line with greater activity of cisplatin in the parent cell line and that of LH6 in the resistant cell line. If the observed in vitro activity of LH6 is confirmed in vivo, it can be seen to have the potential for development as novel platinum based anticancer drug.

Synergism from combinations of tris(benzimidazole) monochloroplatinum(II) chloride with capsaicin, quercetin, curcumin and cisplatin in human ovarian cancer cell lines.

In the present study, synergism in activity from the sequenced combinations of monofunctional platinum tris(benzimidazole)monochloroplatinum(II) chloride (coded as LH4) with capsaicin, quercetin, curcumin and cisplatin was investigated as a function of sequence of administration in a number of human ovarian tumor models. Cellular accumulations of platinum and the levels of platinum-DNA binding were also determined for the 0/0 h and 4/0 sequences of administration. LH4 was found to be more active against the resistant A2780(cisR) and A2780(ZD0473R) cell lines than the parent A2780 cell line. As applied to combinations of LH4 with phytochemicals capsaicin, quercetin and curcumin, bolus administration was found to be most synergistic in both the parent A2780 and the resistant A2780(cisR) cell lines. For the combinations of LH4 with cisplatin, additiveness was observed in both the resistant cell lines but mild synergism was observed in the parent cell line. Greater activity of designed monofunctional platinum LH4 against resistant tumor models and synergism from combinations with phytochemicals indicate that the compound has the potential for development as a novel platinum-based anticancer drug.

Synthesis and activity of three new trinuclear platinums with cis-geometry for terminal metal centres.

BACKGROUND: As compared to cisplatin, trinuclear platinum compounds such as BBR3464 and DH6Cl have an altered spectrum of activity possibly because they form long-range adducts with DNA as against mainly intrastrand 1,2-bifunctional adducts formed by cisplatin and its analogues. Because of the labilizing effect associated with the trans-geometry, the compounds are expected to break down inside the cell thus serving to reduce the number of long-range adducts formed. In contrast, trinuclear platinum complexes with cis-geometry for the terminal metal centres would be less subject to such breakdown and hence may produce a greater number of long-range inter- and intrastrand adducts with the DNA. This paper describes the synthesis and activity against human ovarian tumour models of of three new trinuclear platinum complexes with cis-geometry for terminal platinum centres, coded as QH4, QH7 and QH8. The paper also describes cellular accumulation of platinum, level of drug-DNA binding, and nature of interaction of the compounds with pBR322 plasmid DNA. RESULTS: Methods of synthesis, elemental analysis, spectral studies and molar conductivity measurements provide support to the suggested structures of the compounds. QH4 and QH8 are found to be more cytotoxic than cisplatin against the parental A2780 cell line; QH8 is more active than cisplatin against the resistant A2780cisR and A2780ZD0473R cell lines as well. The least compound QH7 shows a greater activity against the resistant cell lines than the parental cell line; it is most damaging to pBR322 plasmid DNA and most able to induce changes in DNA conformation. The variations in activity of the compounds, changes in intracellular drug accumulation and levels of Pt-DNA binding with the changes in number of planaramine ligands bound to central platinum and the length of the linking diamines, can be seen (1) to illustrate structure-activity relationships and (2) to highlight that the relationship between antitumour activity and interaction with cellular platinophiles including DNA can be quite complex as the cell death is carried out by downstream processes in the cell cycle where many proteins are involved. CONCLUSION: Among the three designed trinuclear platinum complexes with cis-geometry for the terminal metal centres, the most active compound QH8 is found to be more active than cisplatin against the parental A2780 and the resistant A2780cisR and A2780ZD0473R cell lines.

Combinations of platinums and selected phytochemicals as a means of overcoming resistance in ovarian cancer.

Cancer sufferers are often found to use herbal products along with targeted therapy although not much information (whether beneficial or harmful) is available about the effects of such combinations. In this study, we investigated synergism from the combination of platinum drugs and a number of tumour-active phytochemicals including curcumin, epigallocatechin-3-gallate, thymoquinone, genistein, resveratrol, betulinic acid and ursolic acid in three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), as a function of concentration and the sequence of administration. Both the dose-effect curves and combination indices show that the binary combinations of platinum drugs with the phytochemicals exert concentration- and sequence-dependent synergism in the cell lines. Generally the degree of synergism is found to be greater in sequenced administration such as 0/2 h, 2/0 h, 0/4 h and 4/0 h than the bolus. The variation in the nature of the combined drug action from being highly synergistic to antagonistic with the change in sequence of administration clearly indicates that the action of one drug modulates that of the other (towards the induction or inhibition of apoptosis). We have also used sequenced combinations of platinum drugs and bortezomib (a proteasome inhibitor that prevents cisplatin-induced proteasomal degration of copper transporter CTR1) to enhance cellular platinum accumulation and the level of platinum-DNA binding especially in the resistant human ovarian tumour models. Proteomic studies to identify the key proteins associated with platinum resistance are ongoing. We have identified 59 proteins associated with platinum resistance in ovarian tumor models.

Carboplatin and oxaliplatin in sequenced combination with bortezomib in ovarian tumour models.

BACKGROUND: Ovarian cancer remains an on-going challenge mainly due to the development of drug resistance and also because the cancer is likely to have metastasized at the time of diagnosis. Currently, chemotherapy based on platinum drugs such as cisplatin is the primary treatment for the disease. Copper transporter 1 is involved in the transport of cisplatin into the cell, but is also down-regulated by the drug. Bortezomib, a proteasome inhibitor, has been reported to block this platinum-induced down-regulation of CTR1, so that in the presence of bortezomib, the cellular uptake of platinum drugs may be increased. Increased platinum accumulation may result in increased platinum - DNA binding so that the platinum drug in combination with bortezomib may produce enhanced cell kill. METHODS: In this study the efficacy of the sequential combinations of carboplatin, oxaliplatin and a trans-platinum compound coded as CH1 with BORT on the human ovarian A2780, A2780cisR, A2780ZD0473R and SKOV-3 cancer cell lines was evaluated. The levels of cellular platinum accumulation and platinum-DNA binding were determined following the treatment with these combinations. In order to investigate the effect of the combinations of the formation of ROS, the total and oxidized glutathione levels were also determined. RESULTS: Prevention of copper transporter 1 degradation by bortezomib is found to enhance the cellular accumulation of platinum, the level of Platinum - DNA binding and increases oxidative stress especially in the resistant cell lines. CONCLUSIONS: The results suggest that the prevention of CTR1 degradation by bortezomib may be playing a major role in increasing the cellular uptake of platinum drugs and platinum-DNA binding level. Furthermore, the generation of oxidative stress appears to be a major contributor to the enhanced cell kill.

Anti-proliferative and pro-apoptotic effects from sequenced combinations of andrographolide and cisplatin on ovarian cancer cell lines.

Andrographolide (Andro) is a diterpenoid that is isolated from Andrographis paniculata and reported to be active against several cancer cell lines. However, few in-depth studies have been carried out on its effects on ovarian cancer cell lines alone or in combination with cisplatin (Cis), which is commonly used to treat ovarian cancer. The aim of this study was to determine the anti-proliferative and apoptotic effects of Andro administered alone and in combination with Cis in the ovarian A2780 and A2780(cisR) cancer cell lines using five different sequences of administration (Cis/Andro h): 0/0h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The results were evaluated in terms of medium-effect dose (Dm) and combination indices (CI) using the CalcuSyn software. Unlike Cis, whose activity was lower in the resistant A2780(cisR) cell line than in the parent A2780 cell line, Andro was found to be three times more active in the A2780(cisR) cell line as compared to that in A2780 cell line. Synergism was observed when Cis and Andro were administered using the sequences 0/4 h and 4/0 h. The percentage of apoptotic cell death was found to be greater for the 0/4 h combination of Andro and Cis as compared to those values from single-drug treatments. The results may be clinically significant if confirmed in vivo.

Studies on the activity of two Trans-planaramine platinum(II) complexes coded as DH4 and DH5 in human ovarian tumour models.

In this article, we report the synthesis and the in vitro activity of trans-bis(2-methylimidazole)dichloroplatinum(II) (coded as DH4) and trans-(ammino)(2,3-diaminopyridine) dichloroplatinum(II) (coded as DH5) in the human ovarian tumour models. DH4 is less active than cisplatin against the parental A2780 cell line but more active than cisplatin against the resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) line. In contrast, DH5 is less active than cisplatin against all three cell lines. The higher activity of DH4 than cisplatin in the A2780(cisR) cell line is in line with the associated higher platinum-DNA binding level. Whereas cisplatin binds with DNA, forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH4 and DH5 are expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH4 and DH5 are less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than do DH4 and DH5, although DH5 is more damaging to DNA. The difference in the activity of DH4 and DH5, with 2-methylimidazole and 2,3-diaminopyridine respectively as carrier ligands, can be seen to illustrate structure-activity relationships.

Studies on combination of platinum drugs cisplatin and oxaliplatin with phytochemicals anethole and curcumin in ovarian tumour models.

Chemopreventative phytochemicals having antitumour and antioxidant properties can overcome problems of chemoresistance and nonspecific toxicity towards normal cells that are associated with platinum-based chemotherapy against cancer. These agents exert their effects by bringing into play numerous cellular proteins that in turn affect multiple steps in pathways leading to tumourigenesis. In this study, combinations of two cytotoxic phytochemicals anethole and curcumin were applied in binary combination with platinum drugs cisplatin and oxaliplatin to three epithelial ovarian cancer cell lines: A2780 (parent), A2780(cisR) (cisplatin-resistant) and A2780(ZD0473R) (ZD0473-resistant). Cell viability was quantified using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay and the combined drug action was analyzed based on the equations derived by Chou and Talalay (1984). Greatest synergism was observed when the phytochemical was added first followed by the platinum drug 2 h later and additiveness to antagonism in combined drug action was observed when the two compounds were administered as a bolus. If confirmed in vivo, the appropriate sequenced combinations of platinum with the phytochemicals may provide a means of overcoming drug resistance.

Epigallocatechin gallate acts synergistically in combination with cisplatin and designed trans-palladiums in ovarian cancer cells.

In this study, synergism in activity from the sequenced combinations of three trans-palladiums (denoted as TH5, TH6 and TH7) with green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), as well as that with cisplatin, was investigated in a number of human ovarian tumour models as a function of sequence of administration. Cellular accumulation of platinum and palladium, and the levels of platinum-DNA and palladium-DNA binding were also determined for the 0/4 h and 0/0 h sequences of administration. The results of the study show that co-administration of cisplatin with EGCG (0/0 h) produces weak synergism in both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780(cisR)) cell lines whereas (0/4 h) administration produces pronounced synergism in both. In contrast, bolus administration of EGCG with TH5, TH6 and TH7 produces marked antagonism except that with TH5, in the A2780(cisR) cell line, where a mild synergism is observed. In the case of TH5, TH6 and TH7, administration of drugs with a time gap (0/4 h or 4/0 h combinations) produces sequence-dependent synergism in both A2780 and A2780(cisR) cell lines, whereas in the case of cisplatin, marked antagonism is observed with the 4/0 h sequence of administration in the A2780 cell line. Whereas the highly synergistic 0/4 h sequence of combination of cisplatin with EGCG is found to be associated with pronounced cellular accumulation of platinum and a high level of platinum-DNA binding, no such clear trend can be seen for any of the combinations of TH5, TH6 and TH7 with EGCG. The results of the present study provide support to the idea that sequenced combinations of platinum drugs and tumour-active palladium compounds with selected phytochemicals such as EGCG may provide a means of overcoming drug resistance.

Combinations of resveratrol, cisplatin and oxaliplatin applied to human ovarian cancer cells.

In this study, combinations of resveratrol with platinum drugs cisplatin and oxaliplatin were administered to human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cell lines with the aim of offering a means of overcoming drug resistance. Cell viability was quantified using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Combination indices and dose response curves were used as measures of the combined drug action. Greatest synergism was observed when resveratrol was administered first followed by the platinum drug (cisplatin or oxaliplatin) 2 h later, and the least synergism was achieved when the two types of compounds were administered as a bolus. The results can be explained by assuming that the administration of resveratrol 2 h before the platinum drug may sensitize the ovarian cancer cells to platinum-induced apoptosis, thus providing a means of overcoming drug resistance. If the results are confirmed in vivo, they may be significant clinically.

Synergism from combinations of cisplatin and oxaliplatin with quercetin and thymoquinone in human ovarian tumour models.

The development of drug resistance remains one of the major hurdles in cancer chemotherapy, particularly so for ovarian cancer. Combination of drugs acting synergistically in combination can offer a means of overcoming drug resistance. In this study, two tumour-active phytochemicals, quercetin and thymoquinone, were combined with two platinum drugs, cisplatin and oxaliplatin, with the aim of providing a means of overcoming drug resistance. Two human epithelial ovarian cancer cell lines, A2780 and its cisplatin-resistant form (A2780(cisR)) were treated with binary combinations of cisplatin and oxaliplatin with quercetin and thymoquinone using three sequences of administration. Cell viability was quantified using the (MTT) reduction assay. The combined drug action was analysed based on the equations derived by Chou and Talalay (1984). Greatest synergism was observed when the phytochemical was added first followed by platinum drug 2 h later and the least synergism (often additive to antagonistic) was observed when the two compounds were administered as a bolus. It is suggested that the addition of the phytochemical 2 h before platinum drug may sensitize cancer cells to platinum action, thus offering a means of overcoming drug resistance. The results may be highly significant clinically if found to be confirmed in vivo.

Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells.

Drug resistance remains an on-going challenge in ovarian cancer chemotherapy. The objective of this study was to determine the effect on synergism in activity from the sequenced combinations of cisplatin (Cis) with curcumin (Cur) and epigallocatechin-3-gallate (EGCG) in the human ovarian cancer cell lines. The drugs were added in binary combinations: Cis combined with Cur, and Cis combined with EGCG to the human ovarian A2780 and A2780(cisR) cancer cell lines, using five different sequences of administration: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The combination index (CI) was used to assess the combined action of the drugs. CIs <1, =1 and >1 indicated synergism, additiveness and antagonism respectively. Cellular accumulation of platinum and platinum-DNA binding levels from Cis and its combination with the phytochemicals were determined using graphite furnace atomic absorption spectrometry. Addition of Cis 4 h before Cur and EGCG (0/4 h combination) produced the most synergistic outcomes in both the A2780 and A2780(cisR) cell lines. The cellular accumulations of platinum and platinum-DNA binding resulting from the 0/4 h combinations were greater as compared to the values using Cis alone, thus providing an explanation for the synergistic action. When sequenced combinations of Cis with Cur and with EGCG are applied to human ovarian A2780 and A2780(cisR) cancer cell lines, lower concentrations and shorter time gap between the two additions seem to produce a higher cytotoxic effect.

Studies on combinations of platinum with paclitaxel and colchicine in ovarian cancer cell lines.

UNLABELLED: Ovarian cancer remains an ongoing challenge because of the occurrence of resistant forms of tumour for which the drugs fail to function. Combination therapy using drugs with different mechanisms of action offer a means of overcoming drug resistance and reducing the side-effects. In this study, binary combinations of four platinum compounds cisplatin (Cs), oxaliplatin (Ox), YH12 [trans-PtCl(2)(ammino) {imidazo-(1,2-α)pyridine}] and TH1 [{trans-PtCl(NH(3))(2)}(2) {trans-Pt(3-hydroxypyridine)(2)(H(2)N(CH(2)) 6NH(2))(2)}Cl(4)] and two plant-based mitotic inhibitors paclitaxel (Tx) and colchicine (Co) have been used against ovarian cancer cell lines A2780 and A2780(cisR) using five different sequences of addition: 0/0 h, 4/0 h, 0/4 h, 24/0 h and 0/24 h. The strongest synergistic effect was observed when the plant compound (Tx or Co) was added first followed by platinum four hours later with combination index at 50% effect level (fa= 0.5) ranging from 0.03 to 0.36 and 0.10 to 0.72 in A2780 and A2780(cisR) cells respectively. Of all the platinum compounds, Cs showed the greatest synergism when combined with Tx and Co (combination index, CI(50)=0.03 in A2780 and from 0.10 to 0.12 in A2780(cisR)). With the sequence 24/0 h, platinum compounds showed greater synergistic effect with Co than Tx in A2780(cisR). With the sequences 0/4 h and 0/24 h, most of the combinations showed weak synergism to antagonism, especially in A2780(cisR). Antagonism was also observed when the two compounds were added simultaneously, especially in A2780(cisR). CONCLUSION: Binary combinations of platinum compounds Cs, Ox, YH12 and TH1 with plant compounds Tx and Co applied to ovarian cancer cell lines showed sequence- and concentration-dependent synergism. The results may have profound implications in therapy, if found to be true in vivo.