The cellular basis of the efficacy of the trinuclear platinum complex BBR 3464 against cisplatin-resistant cells

doi:10.1016/S0162-0134(99)00142-7

Journal of Inorganic Biochemistry

Volume 77, Issues 1–2, 1 October 1999, Pages 59-64

https://doi.org/10.1016/S0162-0134(99)00142-7 Get rights and content

Abstract

Multinuclear platinum compounds have been designed to circumvent the cellular resistance to conventional mononuclear platinum-based drugs. In this study we performed a comparative study of cisplatin and of the triplatinum complex BBR 3464 in a human osteosarcoma cell system (U2-OS) including an in vitro selected cisplatin-resistant subline (U2-OS/Pt). BBR 3464 was extremely potent in comparison with cisplatin in U2-OS cells and completely overcame resistance of U2-OS/Pt cells. In both cell lines, BBR 3464 accumulation and DNA-bound platinum were higher than those observed for cisplatin. On the contrary, a low frequency of interstrand cross-links after exposure to BBR 3464 was found. Differently from the increase of DNA lesions induced by cisplatin, kinetics studies indicated a low persistence of interstrand cross-link formation for BBR 3464. Western blot analysis of DNA mismatch repair proteins revealed a marked decrease of expression of PMS2 in U2-OS/Pt cells, which also exhibited microsatellite instability. Studies on DNA mismatch repair deficient and proficient colon carcinoma cells were consistent with a lack of influence of the DNA mismatch repair status on BBR 3464 cytotoxicity. In conclusion, the cytotoxic potency and the ability of the triplatinum complex to overcome cisplatin resistance appear to be related to a different mechanism of DNA interaction (formation of different types of drug-induced DNA lesions) as compared to conventional mononuclear complexes.

Introduction

BBR 3464 is a novel trinuclear platinum compound (Fig. 1) which, by virtue of its molecular structure, was expected to produce DNA lesions different from those produced by conventional mononuclear platinum compounds including cisplatin. The central Pt unit does not contribute to covalent DNA binding, but gives a charge and hydrogen-bonding capacity which increases the affinity for DNA [1]. Based on its structural features and multifunctional nature (4+ charges, reactive Pt centres) this drug should be regarded as the representative of a new class of DNA damaging agents.

In a preclinical study we have reported that BBR 3464 is extremely effective in inhibiting the growth of tumour xenografts poorly responsive to cisplatin [2]. However, the cellular basis of BBR 3464 efficacy was not completely elucidated. Therefore, we performed a comparative study of BBR 3464 and cisplatin in cisplatin-sensitive and -resistant cells to define the molecular determinants of response to BBR 3464 and the cellular basis of lack of cross-resistance. For this purpose, we used a human osteosarcoma cell line (U2-OS) and an in vitro selected cisplatin-resistant subline (U2-OS/Pt).

Section snippets

Cell lines and growth conditions

The cisplatin-resistant osteosarcoma cell line U2-0S/Pt was generated by continuous exposure of the U2-OS cell line (ATCC, HTB 96) to increasing concentrations of cisplatin up to 1 μg/ml. Both cell lines were grown in McCoy’s 5A containing 10% fetal calf serum. The hMLH1-deficient human colorectal adenocarcinoma cell line HCT116 and sublines complemented with chromosome 3 (HCT116/chr3) and chromosome 2 (HCT116/chr2) were kindly provided by Dr R. Boland (San Diego, CA). Cell lines were

Results and discussion

The cellular effects of BBR 3464 were studied in a human osteosarcoma cellular model including cisplatin-sensitive and -resistant cells. The U2-OS/Pt cells exhibited a degree of resistance to cisplatin of approximately 6. In U2-OS cells, BBR 3464 displayed a marked cytotoxic potency as compared to cisplatin and a complete lack of cross-resistance was found in U2-OS/Pt cells (Table 1).

To investigate the cellular basis of the capability of BBR 3464 to overcome cisplatin resistance, we performed

Conclusions

The present study indicates that the multinuclear platinum complex, BBR 3464, is a potent cytotoxic agent which overcomes multiple mechanisms of cisplatin resistance. The cellular basis of the cytotoxic potency appears to be related to the extent of cellular accumulation and DNA platination. In particular, the observed amount of DNA binding supports an increased affinity of BBR 3464 for DNA, as expected from the presence of two reactive platinum centres and on the positive charge of the

Abbreviations

ICL	interstrand cross-link
MMR	DNA mismatch repair

Acknowledgements

This work was partially supported by the Consiglio Nazionale delle Ricerche (Progetto Finalizzato ‘Applicazioni Cliniche della Ricerca Oncologica’), the Associazione Italiana Ricerca sul Cancro and the Ministero della Sanità.

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Citation Excerpt :
This approach increases affinity for DNA [69,70]. BBR3564 exhibits in vitro and in vivo potency [59,72,74–79], forming DNA adducts that the repair proteins are unable to recognise [77,78,80]. Partial responses by patients, in phase II clinical trials, together with substantial neutropenia and gastrointestinal toxicity and other side effects limited the maximum tolerated dose [81,82].
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The cellular basis of the efficacy of the trinuclear platinum complex BBR 3464 against cisplatin-resistant cells

Abstract

Introduction

Section snippets

Cell lines and growth conditions

Results and discussion

Conclusions

Abbreviations

Acknowledgements

Curr. Opin. Genet. Dev.

Biochemistry

Br. J. Cancer

Proc. Am. Ass. Cancer Res.

Clin. Cancer Res.

Methods Cancer Res.