Enhanced Accumulation of Cisplatin in Ovarian Cancer Cells from Combination with Wedelolactone and Resulting Inhibition of Multiple Epigenetic Drivers.

PURPOSE: Cisplatin resistance is a major concern in ovarian cancer treatment. The aim of this study was to investigate if wedelolactone could perform better in resistant ovarian cancer cells when used in combination with cisplatin. METHODS: Growth inhibitory potential of wedelolactone and cisplatin was investigated through MTT reduction assay in ovarian cancer cell lines including A2780 (sensitive), A2780cisR (cisplatin resistant) and A2780ZD0473R. Resistance factor (RF) of drugs was determined in these three cell lines. Combination index (CI) was calculated as a measure of combined drug action. Effect of this combination on changes in the cellular accumulation of platinum levels and platinum-DNA binding was also determined in vitro using AutoDock Vina while the effect of wedelolactone on inhibition of possible key culprits of resistance including Chk1, CD73, AT tip60, Nrf2, Brd1, PCAF, IGF1, mTOR1 and HIF2α was investigated in silico. RESULTS: Cisplatin and wedelolactone showed a dose-dependent growth inhibitory effect. RF value of wedelolactone was 1.1 in the case of A2780cisR showing its potential to bring more cell death in cisplatin-resistant cells. CI values were found to vary showing antagonistic to additive outcomes. Additive effect was observed for all sequences of administration (0/0, 0/4 and 4/0 h) in A2780cisR. Enhanced cellular accumulation of cisplatin was observed in parent and resistant cells on combination. Docking results revealed that among the selected oncotargets, Chk1, CD73, Nrf2, PCAF and AT tip60 were more vulnerable to wedelolactone than their respective standard inhibitors. CONCLUSION: These findings have shown that additive outcome of drug combination in A2780cisR and raised levels of platinum accumulation followed a clear pattern. This observation indicates that the presence of wedelolactone might have contributed to sensitize A2780cisR. However, in silico results point to the possible effects of this compound on epigenetic factors involving tumor microenvironment, epithelial mesenchymal transition, and immune-checkpoint kinases.

Synergistic Cytotoxic Effect from Combination of Wedelolactone and Cisplatin in HeLa Cell Line: A Novel Finding.

CONTEXT AND OBJECTIVE: Cisplatin is a platinum drug in current clinical use for the treatment of cervical cancer. However, drug toxicity and resistance are its two major limitations. The aim of this investigation was to test the cytotoxic activity of potential phytochemicals alone and in combination with cisplatin in cervical cancer cells. METHODS: In this study, cytotoxicity of phytochemicals including wedelolactone (WDL), betulinic acid (BA) and epigallocatechin gallate (EGCG) was investigated in human cervical cancer cell line HeLa through 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Combined drug action resulting from the combination of cisplatin with WDL and BA was investigated in the same cell line through median effect principle. The combination index (CI) was taken as a measure of combined drug action. RESULTS: BA resulted in synergistic outcome when co-administered with cisplatin at 0/0 time; (bolus administration) while administration of either drug (cisplatin or BA) four hours before the other (0/4 or 4/0) resulted in antagonistic action. WDL, on the other hand, was found out to be synergistic at any of the applied sequence of drug administration (0/0, 0/4 or 4/0). DISCUSSION AND CONCLUSION: This is the first study reporting cytotoxic activity of WDL in HeLa cells either as single agent or in combination with cisplatin. These results support the idea that sequential combination of cisplatin with WDL and BA may work effectively in cervical cancer cells.

Prospects of Wedelolactone as a Chemotherapeutic Agent in Gynecological Cancers; Clue From its In Vitro and In Silico Investigation.

BACKGROUND: Identification and development of new drug candidates to be used singly or in combination therapy is critical in anticancer research. In recent years, accumulating evidence encouraged us to investigate the anti-proliferative effects of a small and emerging phytochemical Wedelolactone (WDL) in estrogen-dependent and independent multiple gynecological tumor models. OBJECTIVE: The aim of this study was to investigate the growth inhibitory effect of WDL on estrogen- dependent and independent gynecological cell lines and to explore its inhibitory potential towards key targets through in silico study. METHODS: Cytotoxicity of WDL was investigated in human breast and ovarian cancer cell lines (MCF-7 and SKOV3) through 3-(4,5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Epigallocatechingallate (EGCG) was used as reference natural compound while cisplatin was taken as a standard clinical agent. Both WDL and EGCG in combination with cisplatin were also evaluated for their combined growth inhibitory potential in MCF-7 cells. WDL was also evaluated in silico against key factors including braf kinases, CDPK, ERα, aromatase, topoisomerase II and dihydrofolate reductase (DHFR) playing pivotal roles in driving multiple tumors. RESULTS AND DISCUSSION: The IC50 value of WDL was 25.77 ± 4.82 µM and 33.64 ± 1.45 µM in MCF-7 and SKOV-3 respectively. The binding energy order was as follows; WDL: DHFR >Braf kinases > CDPK; aromatase > topoisomerase II> ERα > NFkB > alkaline phosphatase; EGCG dihydrofolatereductase (DHFR) > aromatase >CDPK > topoisomerase II > braf kinases > alkaline phosphatase > CDPK > ERα > NFkB. CONCLUSION: We identified WDL as a cytotoxic agent in breast and ovarian tumor models with the potential to inhibit multiple targets in the oncogenic pathway including estrogen receptor ERα, as depicted through its in silico study. Based on our own research findings and from literature evidence, we conclude that further research should be encouraged to investigate different aspects of wedelolactone as an additional agent to be combined with antiestrogen/endocrine therapy.

Changes in the in vitro activity of platinum drugs when administered in two aliquots.

BACKGROUND: The management of ovarian cancer remains a challenge. Because of the lack of early symptoms, it is often diagnosed at a late stage when it is likely to have metastasized beyond ovaries. Currently, platinum based chemotherapy is the primary treatment for the disease. However acquired drug resistance remains an on-going problem. As cisplatin brings about apoptosis by intrinsic and extrinsic pathways, this study aimed to determine changes in activity of platinum drugs when administered in two aliquots as against a bolus and sought to determine association with changes in GSH, speciation of platinum drugs and changes in protein expression. METHODS: The efficacy of administering cisplatin, carboplatin and oxaliplatin in two aliquots with a time gap was investigated in ovarian A2780, A2780(cisR), A2780(ZD0473R) and SKOV-3 cell lines. The cellular accumulation of platinum, level of platinum - DNA binding and cellular glutathione level were determined, and proteomic studies were carried out to identify key proteins associated with platinum resistance in ovarian A2780(cisR) cancer cell line. RESULTS: Much greater cell kill was observed with solutions left standing at room temperature than with freshly prepared solutions, indicating that the increase in activity on ageing was related to speciation of the drug in solution. Proteomic studies identified 72 proteins that were differentially expressed in A2780 and A2780(cisR) cell lines; 22 of them were restored back to normal levels as a result of synergistic treatments, indicating their relevance in enhanced drug action. CONCLUSIONS: The proteins identified are relevant to several different cellular functions including invasion and metastasis, cell cycle regulation and proliferation, metabolic and biosynthesis processes, stress-related proteins and molecular chaperones, mRNA processing, cellular organization/cytoskeleton, cellular communication and signal transduction. This highlights the multifactorial nature of platinum resistance in which many different proteins with diverse functions play key roles. This means multiple strategies can be harnessed to overcome platinum resistance in ovarian cancer. The results of the studies can be significant both from fundamental and clinical view points.

Synthesis of a monofunctional platinum compound and its activity alone and in combination with phytochemicals in ovarian tumor models.

Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. In this study, a new monofunctional planaramineplatinum(II) complex, namely tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (coded as LH3), was synthesised and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistant A2780 (A2780(ZD0473R)) cancer cell lines, alone and in combination with the phytochemicals curcumin, genistein and resveratrol. Cellular levels of glutathione in A2780 and A2780(cisR) cell lines before and after treatment with LH3 and its combinations with genistein and curcumin were also determined. Interaction of the compounds with salmon sperm DNA, pBR322 plasmid DNA and damage to DNA in A2780 and A2780(cisR) cells due to interaction with LH3-alone and in combination with phytochemicals were also investigated. LH3 was found to be much more active than cisplatin against the resistant tumor models and greatest synergism in activity was observed when combinations of LH3 with genistein and curcumin were administered as a bolus. For combinations of LH3 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were found to be greater in the resistant A2780(cisR) cell line than in the parental A2780 cell line. Greater activity of LH3 than cisplatin against the resistant ovarian cell lines indicates that it may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy.

Synthesis and antitumour activity of a new trinuclear platinum compound [{cis-PtCl(NH3)2µ {trans-Pt(3-hydroxypyridine)2H2N(CH2)5NH2)2}] Cl4 in human ovarian cancer cells.

A trinuclear platinum compound with a cis-geometry for the terminal metal centers coded as QH5 has been synthesized and investigated for activity against the human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines. Cellular accumulation of platinum, level of platinum-DNA binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH5 is found to be more active than cisplatin against all the three cell lines and to have much lower resistant factors than cisplatin. The compound is 2.5-times more active than cisplatin against the A2780(cisR) cell line and 11.5-times more active than cisplatin against A2780(ZD0473R) cell line. When the activity of QH5 in A2780 cell line is compared with its activity in the A2780(ZD0473R) cell line, it is found to be 2.4-times more active against the resistant A2780(ZD0473R) cancer cell line than the parent A2780 cell line, thus indicating that it has been able to overcome mechanisms of resistance operating in the A2780(ZD0473R) cell lines. The higher activity of QH5 as compared to cisplatin is found to be associated with higher platinum accumulation at all time points and high level of platinum-DNA binding at 24 h in all the three human ovarian cancer cell lines. Provided QH5 has the right toxicity profile and its in vitro activity is complemented with sufficient activity in vivo, the compound may have the potential for development as a novel platinum-based anticancer drug targeted to ovarian cancer.

[Study on trace elements of lake sediments by ICP-AES and XRF core scanning].

It is the first time to study sediment of Toson lake in Qaidam Basin. Trace elements including Cd, Cr, Cu, Zn and Pb in lake sediment were measured by ICP-AES method, studied and optimized from different resolution methods respectively, and finally determined a optimum pretreatment system for sediment of Toson lake, namely, HCl-HNO3-HF-HClO4-H2O2 system in the proportions of 5 : 5 : 5 : 1 : 1 was determined. At the same time, the data measured by XRF core scanning were compared, the use of moisture content correction method was analyzed, and the influence of the moisture content on the scanning method was discussed. The results showed that, compared to the background value, the contents of Cd and Zn were a little higher, the content of Cr, Cu and Pb was within the background value limits. XRF core scanning was controlled by sediment elements as well as water content in sediment to some extent. The results by the two methods showed a significant positive correlation, with the correlation coefficient up to 0.673-0.925, and they have a great comparability.

Synthesis and cytotoxicity of three trans-palladium complexes containing planaramine ligands in human ovarian tumor models.

The present study deals with the synthesis, characterization, and activity against human ovarian cancer cell lines A2780, A2780(cisR), A2780(ZD0473R), and SKOV-3 of three trans-planaramine-palladium(II) complexes of the form trans-PdL(2)Cl(2), coded as EH1, EH3, and EH4, for which L = 2-methylpyridine, imidazole, and 1,2-α-imidazopyridine, respectively. The cellular accumulation of palladium, palladium-DNA binding levels, and the nature of interactions of the compounds with salmon sperm and pBR322 plasmid DNA were also determined. All three compounds were found to be less active than cisplatin, but unlike cisplatin they were found to be equally or more active against the resistant cell lines A2780(cisR) and A2780(ZD0473R) than against the parent cell line A2780. Among the three palladium complexes, EH4 (which has the bulkiest carrier ligand) was found to be most active, in line with the highest cellular accumulation of palladium and highest level of palladium-DNA binding resulting from the compound. EH4 was also found to cause the greatest conformational change to pBR322 plasmid DNA. The results of this study illustrate structure-activity relationships; in particular, they support the idea that the decreased reactivity of trans-palladium complexes through the introduction of bulky ligands can make them more active against tumors.

Synthesis and activity of [{Cis-PtCl(NH3)2}2µ{trans-Pt(3-Hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in the human ovarian tumour models.

A novel trinuclear platinum compound with a cis-geometry for terminal metal centres coded as QH1 has been synthesized, characterized and investigated for activity against the human ovarian A2780, A2780cisR and A2780ZD0473R cancer cell lines. The cellular accumulation of platinum, level of platinum-DNA binding and the nature of interaction of the compound with pBR322 plasmid DNA have also been determined. QH1 is found to be more active against the resistant cell lines than the parent cell line, thus indicating that the compound has been able to overcome mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. The high activity of QH1 is associated with high platinum accumulation and high level of platinum-DNA binding in all the three ovarian cancer cell lines. Provided QH1 has the right toxicity profile and its in vitro activity is matched with sufficient activity in vivo, the compound has the potential for development as a novel platinum-based anticancer drug targeted to the ovarian cancer.

Synthesis of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) and its activity in human ovarian tumour models.

UNLABELLED: We report the synthesis and in vitro activity of trans-bis-(2-hydroxypyridine)dichloroplatinum(II) (coded as DH3) in humour ovarian tumour models. The compound is less active than cisplatin against the parent cell line A2780 but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line. DH3 is marginally less active than cisplatin against ZD0473-resistant A2780(ZD0473R) cell line but with a much lower resistance factor than cisplatin. DH3 has higher platinum-DNA binding levels than cisplatin in the A2780 and A2780(ZD0473) cell lines and a lower value in the A2780(cisR) cell line. Even though DH3 has a lower activity than cisplatin, the higher platinum-DNA binding levels observed for DH3 than cisplatin in A2780 and A2780(ZD0473R) cell lines may not be entirely unexpected when we note that the two compounds are likely to differ in their nature of binding with DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH3 is expected to form more 1,2-interstrand Pt(GG) and monofunctional adducts. The higher activity of DH3 than cisplatin in the A2780(cisR) cell line despite its lower level of platinum-DNA binding can also be seen to indicate the complexity of the situation. Although platinum-DNA binding may be an essential requirement for apoptosis, it is not sufficient to cause cell death that is actually brought about by downstream processes in the cycle. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion show that DH3 is less able to prevent BamH1 digestion than is cisplatin, indicating that cisplatin causes a greater conformational change in the DNA than DH3. CONCLUSION: DH3 is less active than cisplatin against the parent cell line A2780, but more so against the cisplatin-resistant A2780(cisR) cell line, thus indicating that it is better able to overcome mechanisms of resistance operating in the A2780(cisR) cell line.

Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines.

Oxaliplatin (Oxa) is a third generation platinum drug currently in clinical use for the treatment against colorectal cancer. Although it has a somewhat different spectrum of activity than cisplatin (Cis), it too has two major limitations, namely problems of side-effects and drug resistance. In this study, combined drug action from the combination of Oxa with the phytochemicals andrographolide (Andro), epigallocatechin-3-gallate (EGCG), chlorophyllin (Chl), colchicines (Col), curcumin (Cur) and paclitaxel (Tax) was evaluated in the human ovarian cancer cell lines A2780 and A2780(cisR). The combination index (CI) was used as a measure of synergism (CI<1), addictiveness (CI=1) and antagonism (CI>1). Generally, all the combinations showed greater synergism at a lower concentration (ED(50)) than at higher concentrations (ED(75) and ED(90)). Oxa in binary combination with Col and Tax showed the highest synergism in both the cancer cell lines, when administered 4 h after the phytochemical, with CI at ED(50) ranging from 0.004 to 0.1. The combination of Oxa with the other phytochemicals generally showed greater synergism when Oxa was administered 4 h before the phytochemical. Appropriately sequenced combination of Oxa with tumor active phytochemicals produces marked synergistic effects in cisplatin resistant as well as non-resistant ovarian cancer cell lines and may offer the means of overcoming drug resistance in ovarian cancer.

Modulation of cisplatin cytotoxicity due to its combination with bortezomib and the nature of its administration.

The widely used anticancer drug cisplatin (CS) is believed to cross the cell membrane by passive diffusion, carrier-mediated transport and pinocytosis. One carrier involved in the transport of CS into the cell is the copper transporter CTR1. However, CS is found to trigger the down-regulation of CTR1 and its proteasomal degradation. The proteasome inhibitor bortezomib (Bort) has been reported to block CS-induced down-regulation of CTR1 so that in the presence of Bort, the cellular uptake of CS may be increased. Increased platinum accumulation may result in increased platinum-DNA binding so that CS in combination with Bort may produce pronounced cell kill. In this study, synergism in activity from the sequenced combination of CS and Bort in human ovarian A2780, A2780(cisR) and A2780(ZD0473R) cancer cell lines was studied. We also investigated the effect on cell kill due to the administration of CS in two aliquots with a time gap. Addition of Bort 2 h before CS was found to produce greater cell kill than the converse and the bolus, especially in the resistant A2780(cisR) and A2780(ZD0473R) cell lines, in line with increased platinum accumulation and platinum-DNA binding levels. Thus, the prevention of CTR1 degradation by Bort may play a significant role, especially in the resistant cell lines. Administration of CS in two aliquots with a time gap was also found to maximise the cell kill in the ovarian cancer cell lines. If such findings are found to be true in vivo, the results may be significant clinically.

Synergism from combination of cisplatin and multicentred platinums coded as DH6Cl and TH1 in the human ovarian tumour models.

Development of drug resistance and the presence of dose-limiting side-effects remain the two main problems in cancer chemotherapy. Combination of drugs with different mechanisms of action can offer a distinct advantage over monotherapy in overcoming drug resistance and reducing the side-effects. In this study synergism in activity from the combinations of cisplatin (Cis) with two multicentred platinum complexes coded as TH1 and DH6Cl in the human ovarian A2780, A2780cisR and A27800473R cancer cell lines had been investigated. Although Cis, TH1 and DH6Cl all bind with nucleobases in the DNA, they differ in the nature of adducts formed and the non-covalent interactions they may undergo. Whereas Cis binds with nucleobases in the DNA forming mainly intrastrand bifunctional adducts such 1,2-Pt(GG) and 1,2-Pt(AG), TH1 and DH6Cl are expected to form mainly interstrand bifunctional G-Pt.....Pt-G adducts with the DNA. It was found that Cis in combination with TH1 and DH6Cl produced both sequence- and concentration-dependent synergism. Generally greater synergism was produced when the two compounds were added at the same time than with a 4 h time gap. For the combination of Cis with TH1, significant synergism was produced only in the parent A2780 cell line but not in the resistant A2780(cisR) and A2780(0473R) cell lines, thus indicating that the combinations of Cis with TH1 would not offer any advantage in overcoming the drug resistance. In contrast, 0/0 h and 4/0 h combinations of Cis and DH6Cl in A2780(cisR) cell line were found to be synergistic, thus indicating that combinations of Cis with DH6Cl may offer a therapeutic advantage. Although both TH1 and DH6Cl are expected to form a number of long-range interstrand G-Pt......Pt-G adducts with nucleobases in the DNA, TH1 and DHCl are expected to differ in their non-covalent interactions with the DNA due to the presence of two 3-hydroxypyridine ligands bound to the central metal ion in TH1 but not in DH6Cl which instead contains two ammino ligands bound to the central palladium ion.

Synergism from combination of cisplatin and a trans-platinum compound in ovarian cancer cell lines.

Development of drug resistance and the presence of dose-limiting side-effects remain two major problems in cancer chemotherapy. Combination of drugs can offer a means of overcoming drug resistance and reducing side-effects. This study investigated synergism in activity from the combinations of cisplatin (Cis) and trans-planaramineplatinum(II) compound YH12 in the human ovarian A2780, A2780(cisR) and A2780(0473R) cancer cell lines. It was found that Cis and YH12 in combination produced both sequence- and concentration-dependent synergism. Addition of Cis first followed by YH12 4 h later produced least synergistic outcomes in all the three cell lines whereas the addition of YH12 first followed by Cis 4 h later and the bolus addition produced much greater synergism. It is believed that as Cis binds with a DNA strand forming intrastrand bifunctional 1,2-Pt(GG) and 1,2-Pt(AG) adducts, the DNA strand is bent. As a result, the subsequent interstrand bifunctional binding of YH12 to the bent DNA would be hampered due to a greater distance mismatch between the two trans-arms of YH12 and the distance between 1,2-interstrand N7(G) and N7(G) positions especially those close to the cisplatin-binding site. This may explain why the 0/4 h addition would be least synergistic in outcome. Conversely, although the interstrand GG binding of YH12 first (that would occur in the 4/0 h and 0/0 h additions), brings about global changes in DNA conformation, it will not significantly affect the subsequent intrastrand bifunctional binding of Cis, so that these modes of addition would result in greater synergistic outcomes. The results of the present study will have implications in the design of combination therapy if confirmed in vivo.

Studies on two new mixed ligand platinum compounds with a trans-geometry.

In this paper we report the synthesis and in vitro activity of two new mixed ligand platinum complexes: trans-[PtCl2(thiazole)(imidazole) [JH3] and trans-[PtCl2(thiazole)(3-hydroxypyridine) [JH4]. Although the compounds are less active than cisplatin against the parent ovarian cancer cell line A2780, they are more active than cisplatin against the resistant cell lines A2780(cisR) and A2780(ZD0473R), thus indicating that JH3 and JH4 have been better able to overcome mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R). When Pt-DNA binding levels at 24 h in A2780, A2780(cisR) and A2780(ZD0473R) cell lines are compared it is found that whereas for cisplatin the values in resistant cell lines are significantly lower than that in the parent cell line, for JH3 and JH4 Pt-DNA binding levels in the parent and resistant cell lines are comparable, thus providing an explanation for variations in activity of the compounds in the three cell lines.

Studies on the synthesis and activity of three tripalladium complexes containing planaramine ligands.

The present study deals with the synthesis, characterization and activity against human cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R) of three tripalladium complexes, MH3, MH4 and MH5, that each have two planaramine ligands bound to the central metal ion. Cellular uptake levels, extent of DNA binding, and nature of interaction with salmon sperm and pBR322 plasmid DNA were determined for each complex. Palladium compounds are much more reactive than their corresponding platinum derivatives, which makes them therapeutically inactive but toxic. However, the results of the present study suggest that significant antitumour activity can be introduced in palladium complexes by lessening their reactivity by the introduction of sterically hindered ligands such as 2-hydroxypyridine, 3-hydroxypyridine and 4-hydroxypyridine. When bound to the central palladium ion, 4-hydroxypyridine appears to be more activating than 2-hydroxypyridine and 3-hydroxypyridine, suggesting that noncovalent interactions, such as hydrogen bonding, may also be key determinants of antitumour activity in addition to the steric effect. While cisplatin binds with DNA to form intrastrand GG adducts that causes local bending of a DNA strand, these planaramine-derived palladium complexes are expected to bind with DNA and form a number of long-range interstrand GG adducts that would cause a global change in DNA conformation, provided the tripalladium cations in MH3, MH4 and MH5 persist under physiological conditions.

Synthesis, activity and binding with DNA of [{trans-PtCl(NH(3))(2)}(2)micro-{trans-Pd(4-hydroxypyridine) (2) (H(2)N(CH(2))(6)NH(2))(2)]Cl(4) (TH8).

This paper describes the synthesis, characterization, cytotoxicity of a new trinuclear Pt-Pd-Pt complex code named TH8 containing two 4-hydroxypyridine ligands bound to the central metal ion. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R), cell uptake, level of DNA-binding and nature of interaction of the compound with pBR322 plasmid DNA have also been determined. TH8 is found to be less active than cisplatin against the parent cell line A2780 but is more active against the cisplatin-resistant cell line A2780(cisR). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH8 are 1.4 and 2.1. The results suggest that TH8 has been better able to overcome the resistance operating in A2780(cisR) cell line. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH8 is expected to bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation.

Synthesis and activity of a trinuclear platinum complex: [{trans-PtCl(NH3)2}2mu-{trans-Pt(3-hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in ovarian cancer cell lines.

This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 plasmid DNA have been determined. TH1 is found to be significantly more cytotoxic than cisplatin - two times more active than cisplatin against the parent cell line A2780, thirteen times more active against the cisplatin-resistant cell line A2780(cisR) and 11.5 times more active against the cell line A2780(ZD0473R). Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780(cisR), and A2780 and A2780(ZD0473R) are 12.9 and 3.0 respectively, the corresponding values for TH1 are 1.98 and 0.5. The results suggest that TH1 has been able to significantly overcome resistance in A2780(cisR) and A2780(ZD0473R) cell lines. Whereas cisplatin binds with DNA forming mainly intrastrand GG adduct that causes local bending of a DNA strand, TH1 should bind with DNA forming mainly interstrand GG adducts that would cause more of a global change in DNA conformation. Provided it has favourable toxicity profile, TH1 has the potential to be developed into a highly active anticancer drug with a wider spectrum of activity than cisplatin.

Studies on the activity of three palladium(II) compounds of the form: trans-PdL2Cl2 where L=2-hydroxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine.

Three planaraminepalladium(II) complexes of the form: trans-PdCl(2)L(2), code named TH5, TH6 and TH7 where L=3-hydroxypyridine, 2-hydroxypyridine and 4-hydroxypyridine respectively have been investigated for antitumour activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R). Although the compounds are generally found to be less active than cisplatin, they are often found to be more active against the resistant cell lines than the parent cell line. Among TH5, TH6 and TH7, TH6 which has two 2-hydroxypyridine non-labile ligands is found to be most active against the three cell lines. Variations in activity of TH5, TH6 and TH7 indicate that non-covalent interactions may be playing a significant role in activity. In particular, the results indicate that small changes in planaramine ligands such as the position of the polar OH group can have a more profound effect on activity of the compounds. Palladium compounds are generally found to be toxic rather tumour active because of much higher reactivity. Low but significant activity of trans-palladium(II) complexes TH5, TH6 and TH7 against the ovarian cancer cell lines indicates that it is believed to be associated with the decrease in their reactivity due to the presence of two sterically hindered planaramine ligands.

Synthesis, characterisation, activities, cell uptake and DNA binding of [[trans-PtCl(NH3)2] [mu-(H2N(CH2)6NH2)] [trans-PdCl(NH3)2](NO3)Cl.

The dinuclear complex: [[trans-PtCl(NH(3))(2)] [mu-(H(2)N(CH(2))(6)NH(2))] [trans-PdCl(NH(3))(2)](NO(3))Cl (code named DHD) has been synthesized and characterized. The activity against human cancer cell lines including ovarian: A2780, A2780(cisR), cell up take, level of binding with DNA and nature of interaction of the compound with pBR322 plasmid and salmon sperm DNAs have been determined. The compound is found to exhibit significant anticancer activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R)--about two times as active as cisplatin against A2780 cell line, about five times as active as cisplatin against A2780(cisR) and A2780(ZD0473R) cell lines. The higher activity of DHD suggests that the compound is able to overcome multiple mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. DHD is believed to form a range of interstrand GG adducts with duplex DNA that induces global changes in the DNA conformation, unlike cisplatin and ZD0473 that form mainly intrastrand adducts that induces a local kink in a DNA strand. Increasing prevention of BamH1 digestion of form I and form II pBR322 plasmid DNA with the increase in concentration of DHD provides support to the idea that the interstrand binding of DHD with pBR322 plasmid DNA brings about global changes in DNA conformation.