In Vitro Evaluation of Oxoplatin: An Oral Platinum(IV) Anticancer Agent

Abstract

Platinum(IV) compounds like oxoplatin (cis, cis, trans-diammine-dichlorido-dihydroxido-platinum(IV))show increased stability and therefore can be applied orally. In a panel of 38 human cancer cell lines this drug induced S-phase arrest and cell death with IC 50 values 2.5-fold higher than cisplatin. Oxoplatin may be converted to cisplatin by intracellular reducing agents, however, exposure to 0.1 M HCl mimicking gastric acid yielded cis-diammine-tetrachlorido-platinum(IV) exhibiting twofold increased activity. Similar results were obtained for another platinum(IV) compound, JM 149 (ammine-dichlorido-(cyclohexylamine)-dihydroxido-platinum(IV)), but not for its parent drug JM 216/satraplatin. Genome-wide expression profiling of H526 small cell lung cancer cells treated with these platinum species revealed clear differences in the expression pattern of affected genes between oxoplatin and cisplatin. In conclusion, oxoplatin constitutes a potent oral agent that is either reduced or converted to distinct active compounds, for example, by gastric acid or acidic areas prevailing in solid tumors, in dependence of the respective pharmaceutical formulation.

Anticancer activity and mode of action of titanocene C

“…Cell cycle arrest induced by titanocene C is clearly distinct from that of platinum-based drugs, which points to different mechanisms of action [17]. Our present findings identify expression of helicases such as topoisomerase I, IIα and MCM4 as main targets of titanocene C leading to cell cycle arrest and downregulation of HIST1H4 core histones.…”

“…Thus, in the present study, NCI-H526 cells were treated with titanocene C, and alterations in gene expression were analyzed using a human gene survey microarray system. Although these data need to be confirmed by PCR and/or immunochemistry, they provide an insight into the cellular pathways affected by the test compound [17]. Treatment of NCI-H526 cells resulted in significant changes in gene expression, affecting a host of transcripts involved in different cellular pathways.…”

“…Therefore, alternative drugs distinct from cisplatin in respect to their modes of action and resistance are urgently needed, especially for SCLC patients. Titanocene C induced accumulation of cells in G1/0 for HL-60 and NCI-H526 cells and in S phase for a SCLC line, clearly distinct from the G2M arrest characteristic of platinum compounds [17,18]. Cross-resistance of titanocene C to the platinum compounds cisplatin and oxoplatin was investigated using highly resistant HL-60 variant cell lines, namely HL-60cis and HL-60oxo, in chemosensitivity assays [19].…”

2208 In vitro cytotoxic activities of the oral platinum(IV) prodrug oxoplatin and HSP90 inhibitor ganetespib against a panel of gastric cancer cell lines

“…However, despite enormous promise and anticancer activity reported to date, none of the HSP90 inhibitors in development has been approved for cancer therapy [12]. Since platinum-based combinations are frequently used for the treatment of metastatic gastric cancer we tested cisplatin and a platinum (IV) derivative, namely oxoplatin, in combination with ganetespib for cytotoxic activity against the gastric cancer cell lines and normal IEC6 cells [9]. Combinational treatment of ganetespib with platinum substances, cis-/oxoplatin, resulted in a marked synergistic cytotoxic effect, except for the normal intestinal epithelial cell lines IEC6.…”

Modulation of oxidative DNA damage and DNA-crosslink formation induced by cis-diammine-tetrachloro-platinum(IV) in the presence of endogenous reductants

“…d,l-1,2-Diamino-cyclohexane-tetrachloro-Pt(IV) has been reported that the reduction mechanism is as follows: the Pt(IV) complex binds to guanine base in DNA and subsequently induces direct-electron transfer between Pt(IV) and guanine base, in which oxidized guanine was observed [19][20][21]. In addition, several researchers have reported that the reduction of Pt(IV) compounds can be accomplished by intracellular reductants such as ascorbic acid (AsA) or thiol-containing species like glutathione (GSH), cysteine and metallothioneins [2,[22][23][24][25]. However, the mechanisms of Pt(IV) reduction and reactivity with DNA in the presence of reductants have not yet been elucidated.…”