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TNBC-Sensitive and-Resistant to Cisplatin  \nMartin Vojtek 1, *,†, Clara B. Martins 2,†, Raquel Ramos 1, Sara Gomes Duarte 1, Isabel M. P. L. V. O. Ferreira 3, Ana L. M. Batista de Carvalho 2, *, M. Paula M. Marques 2,4 and Carmen Diniz 1  \nCitation: Vojtek, M.; Martins, C.B.; Ramos, R.; Duarte, S.G.; Ferreira, I.M.P.L.V.O.; Batista de Carvalho, A.L.M.; Marques, M.P.M.; Diniz, C. Pd(II) and Pt(II) Trinuclear Chelates with Spermidine: Selective Anticancer Activity towards TNBC-Sensitive and-Resistant to Cisplatin. Pharmaceutics 2023, 15, 1205. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)pharmaceutics15041205  \nAcademic Editors: Damiano Cirri and Wukun Liu  \nReceived: 28 February 2023  \nRevised: 30 March 2023  \nAccepted: 6 April 2023  \nPublished: 10 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal  \n2 Molecular Physical-Chemistry R & D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal  \n3 LAQV/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal  \n4 Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3000-456 Coimbra, Portugal  \n* [Correspondence: matovoj@gmail.com](Correspondence: matovoj@gmail.com) (M.V.); [almbc@uc.pt](almbc@uc.pt) (A.L.M.B.d.C.);  \nTel.: +351-220428608 (A.L.M.B.d.C.)† These authors contributed equally to this work.  \nAbstract: Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and constitutes 10–20% of all breast cancer cases. Even though platinum-based drugs such as cisplatin and carboplatin are effective in TNBC patients, their toxicity and development of cancer drug resistance often hamper their clinical use. Hence, novel drug entities with improved tolerability and selectivity profiles, as well as the ability to surpass resistance, are needed. The current study focuses on Pd(II) and Pt(II) trinuclear chelates with spermidine (Pd 3Spd 2 and Pt3Spd 2) for evaluating their antineoplastic activity having been assessed towards (i) cisplatin-resistant TNBC cells (MDAMB-231/R),(ii) cisplatin-sensitive TNBC cells (MDA-MB-231) and (iii) non-cancerous human breast cells (MCF-12A, to assess the cancer selectivity/selectivity index). Additionally, the complexes' ability to overcome acquired resistance (resistance index) was determined. This study revealed that Pd 3Spd 2 activity greatly exceeds that displayed by its Pt analog. In addition, Pd3Spd 2 evidenced a similar antiproliferative activity in both sensitive and resistant TNBC cells (IC 50 values 4.65–8.99 􀀖M and 9.24–13.34 􀀖M, respectively), with a resistance index lower than 2.3 . Moreover, this Pd compound showed a promising selectivity index ratio: >6.28 for MDA-MB-231 cells and >4.59 for MDA-MB- 231/R cells. Altogether, the data presently gathered reveal Pd 3Spd 2 as a new, promising metal-based anticancer agent, which should be further explored for the treatment of TNBC and its cisplatinresistant forms.  \nKeywords: palladium; platinum; cisplatin; therapy; antiproliferative; cell viability; antineoplastic activity; cancer resistance  \n1. Introduction  \nCancer resistance to drugs is driven by the reduction or even the lack of an effective response to drug-induced cancer growth inhibition. Resistance can occur in drug-naïve patients, also known as intri","cbCairuhVcRWQ52B","https://ap.wps.com/l/cbCairuhVcRWQ52B","pdf",4734537,15,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"Why are cisplatin-based treatments limited in TNBC?\",\"answer\":\"Cisplatin can be effective, but toxicity and the development of resistance often restrict its clinical use in TNBC patients.\"},{\"question\":\"Which cell models were used to evaluate the Pd(II) and Pt(II) chelates?\",\"answer\":\"The study tested cisplatin-resistant TNBC cells, cisplatin-sensitive TNBC cells, and non-cancerous human breast cells (MCF-12A) to assess selectivity.\"},{\"question\":\"What key finding distinguishes Pd3Spd2 from the Pt analogue?\",\"answer\":\"Pd3Spd2 activity greatly exceeds that of its Pt counterpart, while maintaining similar antiproliferative activity across sensitive and resistant TNBC cells and exhibiting a resistance index below 2.3.\"}]","Pd(II) and Pt(II) Trinuclear Chelates with Spermidine - Selective Anticancer Activity towards TNBC-Sensitive and-Resistant to Cisplatin | PDF",1790250105,38]