Pd<sub>2</sub>Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice
Martin Vojtek,
Salomé Gonçalves-Monteiro,
Patrícia Šeminská,
Katarína Valová,
Loreto Bellón,
Patrícia Dias-Pereira,
Franklim Marques,
Maria P. M. Marques,
Ana L. M. Batista de Carvalho,
Helder Mota-Filipe,
Isabel M. P. L. V. O. Ferreira,
Carmen Diniz
Affiliations
Martin Vojtek
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Salomé Gonçalves-Monteiro
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Patrícia Šeminská
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Katarína Valová
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Loreto Bellón
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Patrícia Dias-Pereira
ICBAS—Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, 4050-313 Porto, Portugal
Franklim Marques
Clinical Analysis Unit, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Maria P. M. Marques
“Molecular Physical-Chemistry” R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Ana L. M. Batista de Carvalho
“Molecular Physical-Chemistry” R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal
Helder Mota-Filipe
iMed.ULisboa, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
Isabel M. P. L. V. O. Ferreira
LAQV/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Carmen Diniz
LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal
Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg/kg/day) or cisplatin (2 mg/kg/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3–8.3 µM), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5–228.9 µM). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.
