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Manganese complexes as an alternative to platinum in cancer therapy

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Manganese complexes as an alternative to platinum in cancer therapy

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Monday, 07.03.2022
The health of the population is crucial for the development of society. Unfortunately, current health systems are under increasing pressure, greatly aggravated by the Covid-19 pandemic, which, consequently, has made the work of health professionals in the field of oncology difficult. Cancer is the second leading cause of death worldwide and it is estimated that in 2040 there will be 28.4 million new cases of cancer worldwide. Colorectal cancer is one of the leading causes of cancer death in the world and ovarian cancer, despite its lower incidence compared to other types of cancer, is three times more lethal than breast cancer. In 2020, ovarian cancer was responsible for 2.1% of all cancer deaths worldwide and for 408 deaths in Portugal. Platinum compounds are present in more than 50% of chemotherapy treatments. However, its effectiveness is often limited by the development of resistance and by the high systemic toxicity that causes side effects such as neurotoxicity and nephrotoxicity, among others. These limitations motivated the investigation of new complexes with metallic centers other than platinum. Responding to this need, our research team aims to design, synthesize and study the in vitro and in vivo antitumor activity of metallic compounds that can be conceived as real alternatives for application in the fight against cancer. As a result of our research, in this study coordinated by Professor Alexandra R Fernandes, from UCIBIO, NOVA School of Science and Technology, and by Doctor Beatriz Royo and Doctor Oscar Rojas from the Institute of Chemical and Biological Technology, NOVA University of Lisbon, we described two manganese complexes (complexes 1 and 2) with an important cytotoxic effect on ovarian (A2780), colorectal (HCT116) and doxorubicin resistant colorectal (HCT116DOX) cell lines and a significant therapeutic window, given their selectivity/specificity for tumor cells in vitro and in vivo. Our results showed that the cytotoxic effect caused by both complexes is a consequence of the induction of Reactive Oxygen Species (ROS) which, in the case of complex 1, leads to cell death by apoptosis and autophagy, and, in the case of complex 2, leads to cell death by apoptosis.
Our team is strongly committed to the development of safer and more effective oncological treatments, and we are convinced that the knowledge acquired over the last few years, including this work, and that the collaboration with other groups such as Prof. Pedro V. Baptista (Nanomedicine lab, NOVA School of Science and Technology) will allow the translation of some of these most promising metallic compounds for clinical trials.
 

Authors and Affiliations:

Oscar A. Lenis-Rojas1, Beatriz Carvalho2,3, Rui Cabral2,3, Margarida Silva2,3,4, Sofia Friães1, Catarina Roma-Rodrigues2,3, Marta S. H. Meireles1, Clara S. B. Gomes5,6, Jhonathan A. A. Fernández7, Sabela F. Vila8, Juan A. Rubiolo8, Laura Sanchez8,9, Pedro V. Baptista2,3, Alexandra R. Fernandes2,3, Beatriz Royo1

1Instituto de Tecnologia Química e Biológica António Xavier, ITQB, Av. da República, 2780-157 Oeiras, Portugal.

2UCIBIO, Departamento Ciências da Vida, NOVA School of Science and Technology, Campus de Caparica, 2829-516 Caparica, Portugal.

3Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon, 2819-516 Caparica, Portugal

4Imed. Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal

5LAQV-REQUIMTE, Departamento de Química, NOVA School of Science and Technology, 2829-516, Caparica, Portugal.

6Departamento de Química, NOVA School of Science and Technology, UCIBIO, 2829-516 Caparica, Portugal

7Laboratory of Zebrafish, Department of Medical Genetics and Genomic Medicine School of Medical Sciences, University of Campinas (UNICAMP), Campinas, 13083-887, São Paulo, Brazil.

8Departamento de Zoología Genética y Antropología Física, Facultad de Veterinaria, Universidad de Santiago de Compostela, Campus de Lugo, 27002 Lugo, Spain.

9Preclinical Animal Models Group. Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, A Coruña, Spain.

 

Abstract:

The antiproliferative activity of [Mn(CO)3(N^N)Br] (N^N = phendione 1, bipy 3) and of the two newly synthesized Mn complexes [Mn(CO)3(acridine)(phendione)]OTf (2) and [Mn(CO)3(di-triazole)Br] (4) has been evaluated by MTS against three tumor cell lines A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), HCT116doxR (colorectal carcinoma resistant to doxorubicin), and in human dermal fibroblasts. The antiproliferative assay showed a dose-dependent effect higher in complex 1 and 2 with a selectivity toward ovarian carcinoma cell line 21 times higher than in human fibroblasts. Exposure of A2780 cells to IC50 concentrations of complex 1 and 2 led to an increase of reactive oxygen species that led to the activation of cell death mechanisms, namely via intrinsic apoptosis for 2 and autophagy and extrinsic apoptosis for 1. Both complexes do not target DNA or interfere with cell cycle progression but are able to potentiate cell migration and neovascularization (for 2) an indicative that their application might be directed for initial tumor stages to avoid tumor invasion and metastization and opening a new avenue for complex 2 application in regenerative medicine. Interestingly, both complexes do not show toxicity in both in vivo models (CAM and zebrafish).

 

Journal: Journal of Biological Inorganic Chemistry (JBIC)

 

Link: https://link.springer.com/article/10.1007/s00775-021-01910-7

 

 

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