Abstract
Drug resistance represents a major issue in treating breast cancer, despite the identification of novel therapeutic strategies, biomarkers, and subgroups. We have previously identified the LQB-223, 11a-N-Tosyl-5-deoxi-pterocarpan, as a promising compound in sensitizing doxorubicin-resistant breast cancer cells, with little toxicity to non-neoplastic cells. Here, we investigated the mechanisms underlying LQB-223 antitumor effects in 2D and 3D models of breast cancer. MCF-7 and MDA-MB-231 cells had migration and motility profile assessed by wound-healing and phagokinetic track motility assays, respectively. Cytotoxicity in 3D conformation was evaluated by measuring spheroid size and performing acid phosphatase and gelatin migration assays. Protein expression was analyzed by immunoblotting. Our results show that LQB-223, but not doxorubicin treatment, suppressed the migratory and motility capacity of breast cancer cells. In 3D conformation, LQB-223 remarkably decreased cell viability, as well as reduced 3D culture size and migration. Mechanistically, LQB-223-mediated anticancer effects involved decreased proteins levels of XIAP, c-IAP1, and Mcl-1 chemoresistance-related proteins, but not survivin. Survivin knockdown partially potentiated LQB-223-induced cytotoxicity. Additionally, cell treatment with LQB-223 resulted in changes in the mRNA levels of epithelial-mesenchymal transition markers, suggesting that it might modulate cell plasticity. Our data demonstrate that LQB-223 impairs 3D culture growth and migration in 2D and 3D models of breast cancer exhibiting different phenotypes.
Highlights
Breast neoplasia is the leading cause of deaths by cancer, in women worldwide [1]
We found a reduction in cell motility and in the migratory profile of MCF-7 and MDA-MB-231 cells following treatment with LQB-223, which was accompanied by an altered pattern of epithelial-mesenchymal markers
We have previously shown that the LQB-223 compound exhibited cytotoxicity to both non-invasive and invasive breast cancer cells [10]
Summary
Breast neoplasia is the leading cause of deaths by cancer, in women worldwide [1]. Breast tumors are highly heterogeneous, presenting distinct clinical outcomes between molecular subgroups [2,3]. We urge the identification of novel anticancer compounds which might be able to surpass drug resistance mechanisms in breast cancer, with tolerable associated toxicity to normal tissues In this context, the compound 11a-N-Tosyl-5-deoxi-pterocarpan, LQB-223, has been previously demonstrated to sensitize P-glycoprotein-overexpressing multidrug-resistant tumors, with little cytotoxicity to normal cells [9,10]. In 3D conformation, LQB-223 treatment remarkably decreased cell viability, as well as reduced tumor volume, and impaired cell migration These effects were not seemingly observed following cell treatment with DOX, the prototype chemotherapeutic agent for breast cancer. Survivin knockdown could potentiate the LQB-223 cytotoxic effects These results further indicate that LQB-223 impairs tumor growth and migration in 2D and 3D models of breast cancer, exhibiting different phenotypes and points, it as a promising compound against this neoplasia
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