The Anti-tumour Agent, Cisplatin, and its Clinically Ineffective Isomer, Transplatin, Produce Unique Gene Expression Profiles in Human Cells

Abstract

Cisplatin is a DNA-damaging anti-cancer agent that is widely used to treat a range of tumour types. Despite its clinical success, cisplatin treatment is still associated with a number of dose-limiting toxic side effects. The purpose of this study was to clarify the molecular events that are important in the anti-tumour activity of cisplatin, using gene expression profiling techniques. Currently, our incomplete understanding of this drug’s mechanism of action hinders the development of more efficient and less harmful cisplatin-based chemotherapeutics. In this study the effect of cisplatin on gene expression in human foreskin fibroblasts has been investigated using human 19K oligonucleotide microarrays. In addition its clinically inactive isomer, transplatin, was also tested. Dualfluor microarray experiments comparing treated and untreated cells were performed in quadruplicate. Cisplatin treatment was shown to significantly up- or down-regulate a consistent subset of genes. Many of these genes responded similarly to treatment with transplatin, the therapeutically inactive isomer of cisplatin. However, a smaller proportion of these transcripts underwent differential expression changes in response to the two isomers. Some of these genes may constitute part of the DNA damage response induced by cisplatin that is critical for its anti-tumour activity. Ultimately, the identification of gene expression responses unique to clinically active compounds, like cisplatin, could thus greatly benefit the design and development of improved chemotherapeutics.

Molecular structure, IR spectra, and chemical reactivity of cisplatin and transplatin: DFT studies, basis set effect and solvent effect

“…However, because of the same action mechanism as CDDP, there was no great breakthrough on the improvement of toxicity and side effects. Trans-diamminedichloroplatinum (II) (TDDP), the trans-isomer of CDDP, was previously known to be ineffective [5,6]. Due to the different structures of cis-and trans-platinum complexes, they produced different action mechanisms with DNA and in turn led to different biological activities.…”

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

“…Inaccurate measures can also be a consequence of drug isomerism [ 28 , 29 ]. In the case of cisplatin, trans-isomerization impairs its clinical efficacy [ 30 ], while isomerization of cetirizine to levocetirizine [ 28 ] led to the development of a safer and more effective drug alternative.…”

Rhodium(III) Dihalido Complexes: The Effect of Ligand Substitution and Halido Coordination on Increasing Cancer Cell Potency

“…Cisplatin, cis- [Pt­(NH 3 ) 2 Cl 2 ] (CDDP), and its platinum derivatives are still the most frequently used transition metal complexes in the treatment of various cancer types . However, the corresponding trans isomer, transplatin (t rans -[(NH 3 ) 2 Cl 2 Pt]), remains therapeutically inactive. , It has been suggested that the orientation of the cis chlorides is key for therapeutic activity, whereby CDDP forms ∼80% of intrastrand DNA cross-links, while transplatin forms monoadducts and interstrand DNA cross-links. − In 2019 Quiroga et al reported a series of aliphatic amine Pt­(II) complexes and highlighted the cis dichlorido complexes have similar modes of action to cisplatin, while the trans diiodido complexes exhibit different modes of action and activate the cytoplasmic protein BID, suggesting a pro-apoptotic cascade. , Generally, Pt-based therapeutics have poor cancer cell selectivity, which is associated with many adverse side-effects and has led chemotherapy research toward new non Pt-based alternatives such as Ru, Os, Rh, and Ir complexes, − in an attempt to overcome some of these selectivity issues. In particular, organometallic complexes have been prominent, with many compounds exhibiting high potency toward cancerous cells, while remaining nontoxic toward normal cell types, allowing for a more targeted therapy and reduction in patient side effects …”