Jun Qing Yu

Synthesis and Activity of a Trinuclear Platinum Complex: [{trans‐PtCl(NH3)2}2μ‐{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, A2780cisR, and A2780ZD0473R, 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 A2780cisR and 11.5 times more active against the cell line A2780ZD0473R. Whereas the resistance factors for cisplatin as applied to the cell lines A2780 and A2780cisR, and A2780 and A2780ZD0473R 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 A2780cisR and A2780ZD0473R 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.

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, A2780cisR, A2780ZD0473R, and SKOV‐3 of three trans‐planaraminepalladium(II) complexes of the form trans‐PdL2Cl2, 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 A2780cisR and A2780ZD0473R 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.

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, A2780cisR and A2780ZD0473R 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.

Studies on New Platinum Compounds

This chapter provides a review of the activities of a number of recently synthesized planaramineplatinum(II) complexes and platinum compounds with multiple metal centers against human ovarian cancer cell lines. Planaramineplatinum complexes code named YH12 and CH1 are found to be significantly more active than cisplatin in the resistant ovarian cancer cell lines A2780cisR and A2780ZD0473R. The compound code-named CH3 contains three 3-hydroxypyridine ligands bound to platinum(II) and therefore can only form a monofunctional Pt(G) adduct and is found to be significantly active, thus indicating that the formation of bifunctional adducts with DNA may not be an essential requirement for activity. Among compounds containing multiple metal centers, DH6Cl and TH1 are much more active than cisplatin.

Synthesis, Activity and Binding with DNA of [{trans-PtCl(NH ) }2μ-{trans- Pd(4-hydroxypyridine) (H N(CH ) NH ) ]Cl (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.

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.

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

BackgroundThe 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.MethodsThe efficacy of administering cisplatin, carboplatin and oxaliplatin in two aliquots with a time gap was investigated in ovarian A2780, A2780cisR, A2780ZD0473R 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 A2780cisR cancer cell line.ResultsMuch 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 A2780cisR cell lines; 22 of them were restored back to normal levels as a result of synergistic treatments, indicating their relevance in enhanced drug action.ConclusionsThe 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 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-(4-hydroxypyridine)(ammine)dichloroplatinum(II) and its activity in the human ovarian tumour models.

As a part of our continued studies on trans-planaramineplatinum(II) complexes, we report here the synthesis and in vitro activity in the human ovarian tumour models of trans-(4-hydroxypyridine)(ammine)dichloroplatinum(II)] (coded as DH1). Although less active than cisplatin against the parent ovarian A2780 and the resistant A2780cisR and A2780ZD0473R cell lines, it has much lower resistant factors than cisplatin. The results indicate that at the level of its activity, DH1 has been better able to overcome the mechanisms of resistance operating in the A2780cisR and A2780ZD0473R cell lines. When platinum-DNA binding levels at 24 h in the A2780, A2780cisR and A2780ZD0473R cell lines are compared it is found that DH1 has higher levels of platinum binding with the DNA than cisplatin even though it has lower activity than cisplatin. The lack of correlation between activity and the platinum-DNA binding level as applied to cisplatin and DH1 may not be so unexpected when we note that the two compounds will differ in their nature of interaction with the DNA. Whereas cisplatin binds with DNA forming mainly intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts, DH1 is expected to form more of 1,2-interstrand Pt(GG) and monofunctional Pt(G) and Pt(A) adducts, thus bringing about different conformational changes in the DNA. The results of interaction with pBR322 plasmid DNA combined with BamH1 digestion showed that DH1 was less able to prevent BamH1 digestion than cisplatin, indicating that cisplatin caused a greater conformational change in the DNA than DH1. Lower activity of DH1 as compared to analogous trans-platinums containing ligands such as 3-hydroxypyridine, 2-hydroxypyridine and imidazo(1,2-α-pyridine) can be seen to illustrate structureactivity relationships. In particular, it supports the idea that, in trans-planaramineplatinum(II) complexes, the ligands 2- hydroxypyridine, 3-hydroxypyridine and imidazo(1,2-α-pyridine) are much more activating towards antitumour activity than 4-hydroxypyrine.

Abstract 5554: Cisplatin in combination with a potential antiestrogen wedelolactone applied to different gynaecological tumor models

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Estrogens are found to influence aetiology and progression of endocrine/hormone responsive cancers in patient specific manner. The concept of hormonal manipulations dates back to the last half of twentieth century when tamoxifen was approved by FDA as the first selective estrogen receptor modulator (SERM). A significant decline in mortality rate in breast cancer is attributed partly to advancements in chemotherapy and adjuvant hormone therapy. However, toxicities from mild to life threatening including the risk of endometrial cancer, remain a major problem. Hence the need of new and more effective SERMs remains. Phytoestrogens being structurally similar to human estrogens can mimic their effects in vitro and in vivo. Wedelolactone, a naturally occurring coumestan, has recently emerged as a compound of high interest due to its inhibitory effects on various types of cancer cells. Several studies have demonstrated its potential as antiestrogen in MCF-7, Ishikawa and SKOV-3 cancer cells. Toxic side effects and intrinsic and acquired drug resistance remains a major hurdle in chemotherapy with cisplatin in ovarian cancer. Another place where non/low cytotoxic options would be desired relate to patients with elevated CA-125 (false positive elevations not uncommon in ovarian cancer patients) but without other clinical symptoms, in order to minimize the negative impact on quality of life. The aim of this study was to evaluate wedelolactone in different gynaecological models alone and also in combination with platinum drug cisplatin to determine its suitability in adjuvant or palliative settings. Methods: Cytotoxicity of compounds alone and in binary combination against six cancer cell lines (A2780, A2780cisR, A2780ZD0473R, SKOV-3, MCF-7 and HELA-3) was evaluated using MTT reduction assay and combination index (CI) as a measure of combined drug action was calculated using equations of Chou and Talalay (1984). Results: Cisplatin and wedelolactone showed varied but dose dependent apoptotic effects. CI values were found out to vary showing antagonistic to additive to synergistic effects in different tumor models. Discussion: Wedelolactone considered as a natural apoptotic agent was found to inhibit cell growth irrespective of receptor status. Variations in combined drug action indicate that further studies would be needed to get more insights on signal transduction pathways. Conclusion: Wedelolactone can be further tested in different in vitro and in vivo models in the hope of being useful for patients with recurrent gynaecological cancers (especially ovarian). Citation Format: Sadia Sarwar, Jun Qing Yu, Fazlul Huq. Cisplatin in combination with a potential antiestrogen wedelolactone applied to different gynaecological tumor models. [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 5554. doi:10.1158/1538-7445.AM2015-5554