Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells
Triple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which has prompted the search for novel metal-based compounds. Dinuclear palladium(II)-sperm...
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MDPI AG
2022-11-01
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| author | Martin Vojtek Maria P. M. Marques Ana L. M. Batista de Carvalho Helder Mota-Filipe Isabel M. P. L. V. O. Ferreira Carmen Diniz |
| author_facet | Martin Vojtek Maria P. M. Marques Ana L. M. Batista de Carvalho Helder Mota-Filipe Isabel M. P. L. V. O. Ferreira Carmen Diniz |
| author_sort | Martin Vojtek |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which has prompted the search for novel metal-based compounds. Dinuclear palladium(II)-spermine chelate (Pd<sub>2</sub>Spm) has previously shown promising pharmacokinetics and in vivo antitumor effects. However, its impact on chemotherapy-resistant TNBC is still to be addressed. This work developed a cell model of cisplatin resistance and compared the anticancer/antiproliferative effects of cisplatin (reference Pt-based drug) and Pd<sub>2</sub>Spm in TNBC cells sensitive (MDA-MB-231) and resistant to cisplatin (MDA-MB-231/R). Pd<sub>2</sub>Spm displayed a similar antiproliferative potency in MDA-MB-231 and MDA-MB-231/R cells, while cisplatin showed ca. 18-fold lower potency towards MDA-MB-231/R cells. When focusing on cell death, the incubation of Pd<sub>2</sub>Spm with either necrostatin-1 (necroptosis inhibitor), Z-VAD (apoptosis inhibitor), or 3-methyladenine (3-MA, autophagy inhibitor) showed that 3-MA could rescue Pd<sub>2</sub>Spm-induced growth inhibition in MDA-MB-231 and MDA-MB-231/R cells. Furthermore, in MDA-MB-231 cells, Pd<sub>2</sub>Spm triggered higher LC3-II levels and more profound Beclin-1 inhibition than cisplatin. Regarding apoptosis, Pd<sub>2</sub>Spm did not induce the cleavage of caspase-3, and the co-incubation of both Pd<sub>2</sub>Spm and Z-VAD yielded only marginal effects in preventing phosphatidylserine externalization compared to cisplatin. Thus, the present data provide more evidence on Pd<sub>2</sub>Spm’s cell death mechanisms, which trigger a caspase-independent cell death with autophagy involvement. In addition, the potential of Pd<sub>2</sub>Spm to overcome chemotherapy resistance is promising. |
| first_indexed | 2024-03-11T06:06:32Z |
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| institution | Directory Open Access Journal |
| issn | 2673-9992 |
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| spelling | doaj.art-c5e8d751f2284736ada3bbb8be45f61c2023-11-17T12:58:48ZengMDPI AGMedical Sciences Forum2673-99922022-11-0114114210.3390/ECMC2022-13469Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer CellsMartin Vojtek0Maria P. M. Marques1Ana L. M. Batista de Carvalho2Helder Mota-Filipe3Isabel M. P. L. V. O. Ferreira4Carmen Diniz5LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal“Molecular Physical-Chemistry” R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal“Molecular Physical-Chemistry” R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, PortugaliMed.ULisboa, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, PortugalLAQV/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalLAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalTriple-negative breast cancer (TNBC) is an aggressive breast carcinoma with a poor prognosis. Current treatment options with platinum-(Pt)-based chemotherapeutics are limited by toxicity/acquired resistance, which has prompted the search for novel metal-based compounds. Dinuclear palladium(II)-spermine chelate (Pd<sub>2</sub>Spm) has previously shown promising pharmacokinetics and in vivo antitumor effects. However, its impact on chemotherapy-resistant TNBC is still to be addressed. This work developed a cell model of cisplatin resistance and compared the anticancer/antiproliferative effects of cisplatin (reference Pt-based drug) and Pd<sub>2</sub>Spm in TNBC cells sensitive (MDA-MB-231) and resistant to cisplatin (MDA-MB-231/R). Pd<sub>2</sub>Spm displayed a similar antiproliferative potency in MDA-MB-231 and MDA-MB-231/R cells, while cisplatin showed ca. 18-fold lower potency towards MDA-MB-231/R cells. When focusing on cell death, the incubation of Pd<sub>2</sub>Spm with either necrostatin-1 (necroptosis inhibitor), Z-VAD (apoptosis inhibitor), or 3-methyladenine (3-MA, autophagy inhibitor) showed that 3-MA could rescue Pd<sub>2</sub>Spm-induced growth inhibition in MDA-MB-231 and MDA-MB-231/R cells. Furthermore, in MDA-MB-231 cells, Pd<sub>2</sub>Spm triggered higher LC3-II levels and more profound Beclin-1 inhibition than cisplatin. Regarding apoptosis, Pd<sub>2</sub>Spm did not induce the cleavage of caspase-3, and the co-incubation of both Pd<sub>2</sub>Spm and Z-VAD yielded only marginal effects in preventing phosphatidylserine externalization compared to cisplatin. Thus, the present data provide more evidence on Pd<sub>2</sub>Spm’s cell death mechanisms, which trigger a caspase-independent cell death with autophagy involvement. In addition, the potential of Pd<sub>2</sub>Spm to overcome chemotherapy resistance is promising.https://www.mdpi.com/2673-9992/14/1/142breast cancerTNBCcisplatinPd2SpmPd(II)-based drugs |
| spellingShingle | Martin Vojtek Maria P. M. Marques Ana L. M. Batista de Carvalho Helder Mota-Filipe Isabel M. P. L. V. O. Ferreira Carmen Diniz Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells Medical Sciences Forum breast cancer TNBC cisplatin Pd2Spm Pd(II)-based drugs |
| title | Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells |
| title_full | Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells |
| title_fullStr | Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells |
| title_full_unstemmed | Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells |
| title_short | Palladium-Spermine Complex (Pd<sub>2</sub>Spm) Triggers Autophagy and Caspase-Independent Cell Death in Triple-Negative Breast Cancer Cells |
| title_sort | palladium spermine complex pd sub 2 sub spm triggers autophagy and caspase independent cell death in triple negative breast cancer cells |
| topic | breast cancer TNBC cisplatin Pd2Spm Pd(II)-based drugs |
| url | https://www.mdpi.com/2673-9992/14/1/142 |
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