Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy

Tina Riedel,Hans-Beat Ris,Lucas Liaudet,Paul J Dyson,Thorsten Krueger,Hubert Van Den Bergh,Jean Y Perentes,Sabrina Cavin

doi:10.1038/s41598-018-28589-2

Abstract

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

Highlights

Malignant pleural mesothelioma is an aggressive cancer for which curative treatments are not available at present
We found that Poly(ADP-Ribose) Polymerase type 1 (PARP-1) activity was inhibited by RAPTA with an IC50 of 400 μM (Fig S1A)
It is noteworthy that PARP-1 has been shown to be involved in the synthesis of vascular endothelial growth factor (VEGF)[20,21]

Summary

Introduction

Malignant pleural mesothelioma is an aggressive cancer for which curative treatments are not available at present. Jain et al first demonstrated that anti-angiogenic therapy at low doses could normalize the vasculature of solid tumors leaving behind a more mature and functional vessel network by selectively pruning immature blood vessels[7,8] This process enhances tumor oxygenation and drug transport, improving the effect of radiation- and www.nature.com/scientificreports/. Based on the moderate anti-angiogenic activity and low in vitro cytotoxicity on cancer and endothelial cells, we hypothesized that these drug properties would be desirable and could be explored to favor vascular normalization without risking too high anti-angiogenic activity and excessive vessel pruning With this objective, we assessed the impact of RAPTA-T [Ru(η6-toluene)(PTA)Cl2] treatment on the tumor vascular morphology and function in a murine pleural mesothelioma model by real time imaging. These results suggest a chemotherapeutic combination therapy with RAPTA-T as a novel option in resectable (as neoadjuvant therapy) and advanced (as palliative therapy) mesothelioma or for the management of other solid tumor cancer types

Methods

Results

Conclusion