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Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice
Martin Vojtek1, Salomé Gonçalves-Monteiro1, Patrícia Šeminská1
1LAQV/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
Abstract:
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.
Insights
Pd2Spm, a palladium(II)-spermine chelate, shows potent anticancer effects against triple-negative breast cancer (TNBC) with reduced toxicity compared to cisplatin. This agent demonstrates promising selectivity and in vivo antitumor activity for TNBC treatment.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Triple-negative breast cancer (TNBC) presents a poor prognosis with limited therapeutic options.
- Metal-based drugs, such as cisplatin, are used in cancer therapy but can cause significant systemic toxicity.
- Dinuclear palladium(II)-spermine chelates represent a novel class of anticancer agents.
Purpose of the Study:
- To evaluate the in vitro and in vivo anticancer efficacy and toxicity of Pd2Spm against TNBC.
- To compare the effects of Pd2Spm with cisplatin, a standard chemotherapeutic agent.
Main Methods:
- In vitro studies utilized MDA-MB-231 (TNBC) and MCF-12A (non-cancerous) cells for antiproliferative assays, and chorioallantoic membrane (CAM) assays for antiangiogenic and antimigratory assessments.
- In vivo efficacy was assessed in mice bearing MDA-MB-231 tumors treated with Pd2Spm or cisplatin.
- Tumor growth, proliferation markers (Ki-67, mitotic figures), DNA damage, and systemic toxicity (hematotoxicity, weight loss) were evaluated.
Main Results:
- Pd2Spm exhibited selective antiproliferative activity against MDA-MB-231 cells (IC50: 7.3–8.3 µM) with significantly lower toxicity to MCF-12A cells (IC50: 89.5–228.9 µM).
- Pd2Spm demonstrated potent inhibition of cell migration, angiogenesis, and VEGF secretion, comparable to cisplatin.
- In vivo, Pd2Spm significantly reduced tumor growth, proliferation, and DNA damage, mirroring cisplatin's efficacy.
- Crucially, Pd2Spm treatment did not induce the systemic toxicity (hematotoxicity, weight loss) observed with cisplatin.
Conclusions:
- Pd2Spm displays promising anticancer selectivity and potent in vivo antitumor activity against TNBC.
- The agent shows a favorable safety profile with significantly lower systemic toxicity compared to cisplatin.
- Pd2Spm represents a potential novel palladium(II) drug candidate for treating TNBC and other low-prognosis cancers.
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