Platinum Complexes in Colorectal Cancer and Other Solid Tumors

Abstract

Cisplatin is one of the most commonly used drugs for the treatment of various solid neoplasms, including testicular, lung, ovarian, head and neck, and bladder cancers. Unfortunately, the therapeutic efficacy of cisplatin against colorectal cancer is poor. Various mechanisms appear to contribute to cisplatin resistance in cancer cells, including reduced drug accumulation, enhanced drug detoxification, modulation of DNA repair mechanisms, and finally alterations in cisplatin DNA damage signaling preventing apoptosis in cancer cells. Regarding colorectal cancer, defects in mismatch repair and altered p53-mediated DNA damage signaling are the main factors controlling the resistance phenotype. In particular, p53 inactivation appears to be associated with chemoresistance and poor prognosis. To overcome resistance in cancers, several strategies can be envisaged. Improved cisplatin analogues, which retain activity in resistant cancer, might be applied. Targeting p53-mediated DNA damage signaling provides another therapeutic strategy to circumvent cisplatin resistance. This review provides an overview on the DNA repair pathways involved in the processing of cisplatin damage and will describe signal transduction from cisplatin DNA lesions, with special attention given to colorectal cancer cells. Furthermore, examples for improved platinum compounds and biochemical modulators of cisplatin DNA damage signaling will be presented in the context of colon cancer therapy.

Keywords: colorectal cancer; mismatch repair defect; p53 signaling; platinum drugs.

Figure 1

Chemical structures of the clinically approved platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin.

Figure 2

Mechanism of human nucleotide excision repair. The repair proteins XPC-hHR23B and UV-DDB detect and bind to the DNA lesion (red triangle). The transcription factor TFIIH with its helicase subunits XPB and XPD is recruited to the damage, leading to local unwinding of the DNA around the lesion. A pre-incision complex is formed by recruitment of XPA, RPA, and XPG, followed by incisions on both sides of the damage, mediated by the endonucleases XPG and ERCC1-XPF complex. DNA polymerase δ/ε, supported by PCNA and RFC, catalyze DNA re-synthesis, the nick is sealed by DNA ligase I.

Figure 3

Mechanism of human mismatch repair. In addition, hMutSα/hMutSβ detect and bind to DNA mismatches or small loops. The hMutLα is recruited, followed by RFC-mediated loading of PCNA onto DNA. EXO1 binds and catalyzes excision of nucleotides beyond the mismatch/loop, followed by Polδ-catalyzed re-synthesis and DNA ligation.

Figure 4

The p53-mediated DNA damage response. Cisplatin-induced DNA damage activates ATM/Chk2 and/or ATR/Chk1, which leads to phosphorylation of p53. Activated p53 induces expression of genes related to the cell cycle control allowing time for DNA repair. If the amount of damage exceeds the cellular repair capacity, apoptosis-related genes will be expressed leading to apoptotic cell death. Futile mismatch repair (MMR) also contributes to cisplatin-induced apoptosis.

Figure 5

Targeting cisplatin resistance in colorectal cancer cells. Cisplatin-derived Pt (II) and Pt (IV) complexes induce structurally different DNA lesions resulting in a different mode of action compared to cisplatin and hence cell death in cisplatin-resistant colorectal cancer cells. Interfering with the DNA repair via activation of mismatch repair (MMR) or inactivation of double strand break (DSB) repair and targeting cisplatin damage signaling by activation of p53 or inactivation of cell cycle checkpoint control the increase in activity of cisplatin and lead to cell death in colorectal cancer cells.