Unraveling survivin expression in chronic myeloid leukemia: Molecular interactions and clinical implications.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the BCR-ABL oncoprotein, known to drive leukemogenesis by orchestrating multiple signaling pathways ultimately involved in cell survival. Despite successful response rates of CML patients to tyrosine kinase inhibitors (TKIs), resistance eventually arises due to BCR-ABL-dependent and independent mechanisms. Survivin is an inhibitor of apoptosis protein acting in the interface between apoptosis deregulation and cell cycle progression. In CML, high levels of survivin have been associated with late stages of disease and therapy resistance. In this review, we provide an overview of important aspects concerning survivin subcellular localization and expression pattern in CML patients and cell lines. Moreover, we highlight the relevance of molecular networks involving survivin for disease progression and treatment resistance. Finally, we discuss the mechanisms accounting for survivin overexpression, as well as novel therapeutic interventions that have been designed to counteract survivin-associated malignancy in CML.

The LQB-223 Compound Modulates Antiapoptotic Proteins and Impairs Breast Cancer Cell Growth and Migration.

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.

11a-N-Tosyl-5-deoxi-pterocarpan, LQB-223, a novel compound with potent antineoplastic activity toward breast cancer cells with different phenotypes.

UNLABELLED: Multidrug resistance is the major obstacle for successful treatment of breast cancer, prompting the investigation of novel anticancer compounds. PURPOSE: In this study, we tested whether LQB-223, an 11a-N-Tosyl-5-deoxi-pterocarpan newly synthesized compound, could be effective toward breast cancer cells. METHODS: Human breast cell lines MCF-7, MDA-MB-231, HB4a and MCF-7 Dox(R) were used as models for this study. Cell culture, MTT and clonogenic assay, flow cytometry and Western blotting were performed. RESULTS: The LQB-223 decreased cell viability, inhibited colony formation and induced an expressive G2/M arrest in breast cancer cells. There was an induction in p53 and p21(Cip1) protein levels following treatment of wild-type p53 MCF-7 cells, which was not observed in the mutant p53 MDA-MB-231 cell line, providing evidence that the compound might act to modulate the cell cycle regardless of p53 status. In addition, LQB-223 resulted in decreased procaspase levels and increased annexin V staining, suggesting that the apoptotic cascade is also triggered. Importantly, LQB-223 treatment was shown to be less cytotoxic to non-neoplastic breast cells than docetaxel and doxorubicin. Strikingly, exposure of doxorubicin-resistant MCF-7-Dox(R) cells to LQB-223 resulted in suppression of cell viability and proliferation in levels comparable to MCF-7. Of note, MCF-7-Dox(R) cells have an elevated expression of the P-glycoprotein efflux pump when compared to MCF-7. CONCLUSION: Together, these results show that LQB-223 mediates cytotoxic effects in sensitive and resistant breast cancer cells, while presenting low toxicity to non-neoplastic cells. The new compound might represent a potential strategy to induce toxicity in breast cancer cells, especially chemoresistant cells.