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Article

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

1
Department of Oncology, University of Turin, Via Santena 5/bis, 10126 Turin, Italy
2
Department of Pharmacy-Drug Sciences, University of Bari “A. Moro”, Via Orabona 4, 70125 Bari, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(9), 3333; https://doi.org/10.3390/ijms21093333
Received: 30 March 2020 / Revised: 2 May 2020 / Accepted: 5 May 2020 / Published: 8 May 2020
Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, F397, F400, and F421, acting as CS-promoting agents. We deepened their CS mechanisms in the “pure” model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors. View Full-Text
Keywords: collateral sensitivity; MDR; MRP1; resistant tumors; lung tumors; ROS collateral sensitivity; MDR; MRP1; resistant tumors; lung tumors; ROS
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MDPI and ACS Style

Riganti, C.; Giampietro, R.; Kopecka, J.; Costamagna, C.; Abatematteo, F.S.; Contino, M.; Abate, C. MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor. Int. J. Mol. Sci. 2020, 21, 3333. https://doi.org/10.3390/ijms21093333

AMA Style

Riganti C, Giampietro R, Kopecka J, Costamagna C, Abatematteo FS, Contino M, Abate C. MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor. International Journal of Molecular Sciences. 2020; 21(9):3333. https://doi.org/10.3390/ijms21093333

Chicago/Turabian Style

Riganti, Chiara, Roberta Giampietro, Joanna Kopecka, Costanzo Costamagna, Francesca S. Abatematteo, Marialessandra Contino, and Carmen Abate. 2020. "MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor" International Journal of Molecular Sciences 21, no. 9: 3333. https://doi.org/10.3390/ijms21093333

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