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.
Highlights
Introduction distributed under the terms andFemale breast cancer is currently the most commonly diagnosed cancer and the leading type of cancer death in women worldwide, with 2.3 million new cases having been diagnosed in 2020 [1]
triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor and progesterone receptor, as well as HER2 overexpression, and disproportionally affects women with African or Indian ancestry, who show higher incidence of TNBC compared to other breast cancer subtypes [2]
TNBC is associated with poorer prognosis than other subtypes of breast cancer, mainly due to higher frequency of metastasis, higher relapse rates and limited treatment options, with no conventional receptor-targeting therapeutics available compared to other breast cancer subtypes
Summary
Introduction distributed under the terms andFemale breast cancer is currently the most commonly diagnosed cancer and the leading type of cancer death in women worldwide, with 2.3 million new cases having been diagnosed in 2020 [1]. Breast cancer is a highly heterogeneous disease that presents several subtypes with different treatment success and survival prognosis. Biomedicines 2022, 10, 210 breast cancer (TNBC) stands out as the most aggressive breast cancer subtype, constituting. TNBC is characterized by the absence of estrogen receptor and progesterone receptor, as well as HER2 overexpression, and disproportionally affects women with African or Indian ancestry, who show higher incidence of TNBC compared to other breast cancer subtypes [2]. TNBC is associated with poorer prognosis than other subtypes of breast cancer, mainly due to higher frequency of metastasis, higher relapse rates and limited treatment options, with no conventional receptor-targeting therapeutics available compared to other breast cancer subtypes. The most frequent unintended outcomes of platinum-based therapy are related to myelosuppression, gastrointestinal reactions and damage of liver and kidney functions, which may be mitigated to certain level by the pre-hydration of patients and other supporting measures [6]
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