http://europepmc.org/articles/PMC4146684?pdf=render

Cisplatin in cancer therapy: molecular mechanisms of action

The platinum derivative cis-diamminedichloroplatinum(II), best known as cisplatin, is currently employed for the clinical management of patients affected by testicular, ovarian, head and neck, colorectal, bladder and lung cancers. For a long time, the antineoplastic effects of cisplatin have been fully ascribed to its ability to generate unrepairable DNA lesions, hence inducing either a permanent proliferative arrest known as cellular senescence or the mitochondrial pathway of apoptosis. Accumulating evidence now suggests that the cytostatic and cytotoxic activity of cisplatin involves both a nuclear and a cytoplasmic component. Despite the unresolved issues regarding its mechanism of action, the administration of cisplatin is generally associated with high rates of clinical responses. However, in the vast majority of cases, malignant cells exposed to cisplatin activate a multipronged adaptive response that renders them less susceptible to the antiproliferative and cytotoxic effects of the drug, and eventually resume proliferation. Thus, a large fraction of cisplatin-treated patients is destined to experience therapeutic failure and tumor recurrence. Throughout the last four decades great efforts have been devoted to the characterization of the molecular mechanisms whereby neoplastic cells progressively lose their sensitivity to cisplatin. The advent of high-content and high-throughput screening technologies has accelerated the discovery of cell-intrinsic and cell-extrinsic pathways that may be targeted to prevent or reverse cisplatin resistance in cancer patients. Still, the multifactorial and redundant nature of this phenomenon poses a significant barrier against the identification of effective chemosensitization strategies. Here, we discuss recent systems biology studies aimed at deconvoluting the complex circuitries that underpin cisplatin resistance, and how their findings might drive the development of rational approaches to tackle this clinically relevant problem.

/pdf/systems-biology-of-cisplatin-resistance-past-present-and-cpstnu2drj.pdf

Systems biology of cisplatin resistance: past, present and future

The demonstration in the 1960's that cis-diamminedichloroplatinum(II), or cisplatin, inhibits cellular division of Escherichia coli1 led to the subsequent discovery that this simple coordination compound is also an effective antitumor agent in mouse models.2 Subsequent studies validated cisplatin as an effective anticancer agent in humans as well,3–7 and FDA approval of cisplatin for the treatment of metastatic ovarian and testicular cancers was granted in 1978.8 Its introduction as a chemotherapeutic agent significantly improved the survival outlook for many cancer patients; the cure rate for testicular cancer before the approval of cisplatin was less than 10%, significantly lower than the 90% cure rate attained with modern platinum chemotherapy.9,10

Cisplatin kills cancer cells primarily by cross-linking DNA and inhibiting transcription.11 The chemical origin of this process begins when cisplatin enters the cell and undergoes aquation involving loss of one or both chloride ligands. The resulting platinum(II) aqua complexes are potent electrophiles that readily react with a number of biological ligands with loss of the bound water molecules. The purine bases of nucleic acids are strongly nucleophilic at the N7 position. Thus, cisplatin binds readily to DNA, forming primarily bifunctional adducts with loss of both chloride ligands. The major cisplatin-DNA adduct is the intrastrand 1,2-d(GpG) cross-link, which accounts for 60–65% of the bound platinum.12 The resulting Pt-DNA adducts, which distort and bend the DNA structure,13–15 impede transcription.16 The downstream effects of transcription inhibition ultimately lead to cell death.

Despite its great curative success in testicular cancer, cisplatin is not universally effective in other cancer types and induces a number of toxic side effects.17–19 Additionally, certain cancers are resistant to cisplatin therapy. This resistance is either intrinsic or developed during prolonged treatment.20,21 To circumvent these problems, new platinum complexes have been pursued and investigated for their antitumor properties. Although well over a thousand complexes have been prepared and tested thus far,22 only two other platinum drugs are approved for clinical use worldwide, and three additional compounds are approved for regional use in Asia.23 These complexes, displayed in Chart 1, operate with a mechanism of action similar to that of cisplatin, which involves DNA binding and transcription inhibition.






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Chart 1


Chemical structures of the clinically used platinum-based anticancer drugs. The top three complexes, cisplatin, carboplatin, and oxaliplatin, are approved for use worldwide. The bottom three complexes, nedaplatin, lobaplatin, and heptaplatin, are approved for use in Japan, China, and Korea, respectively.

/pdf/synthetic-methods-for-the-preparation-of-platinum-anticancer-4et0np31b8.pdf

Synthetic Methods for the Preparation of Platinum Anticancer Complexes

Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies

While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we a...

Toward Multi-Targeted Platinum and Ruthenium Drugs-A New Paradigm in Cancer Drug Treatment Regimens?

Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

Acquired drug resistance in cancer continues to be a challenge in cancer therapy, in part due to overexpression of the drug efflux transporter P-glycoprotein (P-gp, MDR1, ABCB1). NSC73306 is a thiosemicarbazone compound that displays greater toxicity against cells expressing functional P-gp than against other cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (CTR1, SLC31A1). Overexpression of P-gp sensitizes LLC-PK1 cells to NSC73306. Cisplatin (IC50 = 77 μM), cyclosporin A (IC50 = 500 μM), and verapamil (IC50 = 700 μM) inhibited cellular accumulation of [3H]NSC73306. Cellular hypertoxicity of NSC73306 to P-gp-expressing cells was inhibited by cisplatin in a dose-dependent manner. Cells transiently expressing the cisplatin uptake transporter CTR1 (SLC31A1) showed increased [3H]NSC73306 accumulation. In contrast, CTR1 knockdown decreased [3H]NSC73306 accumulation. The presence of NSC73306 reduced CTR1 levels, similar to the negative ...

https://pubs.acs.org/doi/pdf/10.1021/mp500114e

Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306.

Lynn M. Pouliot

Papers

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

Uptake of compounds that selectively kill multidrug-resistant cells: the copper transporter SLC31A1 (CTR1) increases cellular accumulation of the thiosemicarbazone NSC73306.