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Article

Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells

by
Jorge Melones-Herrero
1,2,3,
Patricia Delgado-Aliseda
1,2,3,
Sofía Figueiras
1,2,3,
Javier Velázquez-Gutiérrez
1,2,
Adoración Gomez Quiroga
4,5,
Carmela Calés
1,2,3 and
Isabel Sánchez-Pérez
1,2,3,6,7,*
1
Department of Biochemistry, School of Medicine, Autonomous University of Madrid (UAM), 28029 Madrid, Spain
2
Instituto de Investigaciones Biomédicas “Sols-Morreale” (IIBM), CSIC-UAM, 28029 Madrid, Spain
3
Biomarkers and Personalized Approach to Cancer (BioPAC) Group, Area 3 Cancer-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
4
Department of Inorganic Chemistry, School of Sciences, Autonomous University of Madrid (UAM), 28049 Madrid, Spain
5
Institute for Advance Research in Chemistry, Autonomous University of Madrid (UAM), 28049 Madrid, Spain
6
Centro de Investigación Biomédica en Red, Área Rare Diseases, CIBERER-ISCIII, 28029 Madrid, Spain
7
Unidad Asociada de Biomedicina, UCLM-CSIC, 28029 Madrid, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(14), 7739; https://doi.org/10.3390/ijms25147739
Submission received: 21 May 2024 / Revised: 1 July 2024 / Accepted: 10 July 2024 / Published: 15 July 2024
(This article belongs to the Section Molecular Biology)
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Abstract

Gastric cancer prognosis is still notably poor despite efforts made to improve diagnosis and treatment of the disease. Chemotherapy based on platinum agents is generally used, regardless of the fact that drug toxicity leads to limited clinical efficacy. In order to overcome these problems, our group has been working on the synthesis and study of trans platinum (II) complexes. Here, we explore the potential use of two phosphine-based agents with the general formula trans-[Pt(amine)Cl2(PPh3)], called P1 and P2 (with dimethylamine or isopropylamine, respectively). A cytotoxicity analysis showed that P1 and especially P2 decrease cell viability. Specifically, P2 exhibits higher activity than cisplatin in gastric cancer cells while its toxicity in healthy cells is slightly lower. Both complexes generate Reactive Oxygen Species, produce DNA damage and mitochondrial membrane depolarization, and finally lead to induced apoptosis. Thus, an intrinsic apoptotic pathway emerges as the main type of cell death through the activation of BAX/BAK and BIM and the degradation of MCL1. Additionally, we demonstrate here that P2 produces endoplasmic reticulum stress and activates the Unfolded Protein Response, which also relates to the impairment observed in autophagy markers such as p62 and LC3. Although further studies in other biological models are needed, these results report the biomolecular mechanism of action of these Pt(II)-phosphine prototypes, thus highlighting their potential as novel and effective therapies.
Keywords: platinum complexes; phosphine; gastric cancer; apoptosis; mitochondria; ER stress platinum complexes; phosphine; gastric cancer; apoptosis; mitochondria; ER stress

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MDPI and ACS Style

Melones-Herrero, J.; Delgado-Aliseda, P.; Figueiras, S.; Velázquez-Gutiérrez, J.; Quiroga, A.G.; Calés, C.; Sánchez-Pérez, I. Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. Int. J. Mol. Sci. 2024, 25, 7739. https://doi.org/10.3390/ijms25147739

AMA Style

Melones-Herrero J, Delgado-Aliseda P, Figueiras S, Velázquez-Gutiérrez J, Quiroga AG, Calés C, Sánchez-Pérez I. Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. International Journal of Molecular Sciences. 2024; 25(14):7739. https://doi.org/10.3390/ijms25147739

Chicago/Turabian Style

Melones-Herrero, Jorge, Patricia Delgado-Aliseda, Sofía Figueiras, Javier Velázquez-Gutiérrez, Adoración Gomez Quiroga, Carmela Calés, and Isabel Sánchez-Pérez. 2024. "Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells" International Journal of Molecular Sciences 25, no. 14: 7739. https://doi.org/10.3390/ijms25147739

APA Style

Melones-Herrero, J., Delgado-Aliseda, P., Figueiras, S., Velázquez-Gutiérrez, J., Quiroga, A. G., Calés, C., & Sánchez-Pérez, I. (2024). Trans-[Pt(amine)Cl2(PPh3)] Complexes Target Mitochondria and Endoplasmic Reticulum in Gastric Cancer Cells. International Journal of Molecular Sciences, 25(14), 7739. https://doi.org/10.3390/ijms25147739

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