Lemos Lauana Greicy Tonon, Nestal de Moraes Gabriela, Delbue Deborah, Vasconcelos Flavia da Cunha, Bernardo Paula Sabbo, Lam Eric W-F, Buarque Camilla Djenne, Costa Paulo Ribeiro, Maia Raquel Ciuvalschi
Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.
Programa de Pós-Graduação Strictu Sensu em Oncologia, INCA, Rio de Janeiro, Brazil.
J Cancer Res Clin Oncol. 2016 Oct;142(10):2119-30. doi: 10.1007/s00432-016-2212-6. Epub 2016 Aug 12.
Multidrug resistance is the major obstacle for successful treatment of breast cancer, prompting the investigation of novel anticancer compounds.
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.
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.
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.
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.
多药耐药是乳腺癌成功治疗的主要障碍，这促使人们对新型抗癌化合物进行研究。
在本研究中，我们测试了新合成的化合物11a-N-对甲苯磺酰基-5-脱氧紫檀素（LQB-223）对乳腺癌细胞是否有效。
使用人乳腺癌细胞系MCF-7、MDA-MB-231、HB4a和MCF-7 Dox(R)作为本研究的模型。进行了细胞培养、MTT和克隆形成试验、流式细胞术和蛋白质印迹分析。
LQB-223降低了乳腺癌细胞的活力，抑制了集落形成，并诱导了明显的G2/M期阻滞。野生型p53的MCF-7细胞经处理后，p53和p21(Cip1)蛋白水平升高，而在突变型p53的MDA-MB-231细胞系中未观察到这种现象，这表明该化合物可能无论p53状态如何都能调节细胞周期。此外，LQB-223导致procaspase水平降低和膜联蛋白V染色增加，表明凋亡级联反应也被触发。重要的是，与多西他赛和阿霉素相比，LQB-223对非肿瘤性乳腺细胞的细胞毒性较小。令人惊讶的是，将阿霉素耐药的MCF-7-Dox(R)细胞暴露于LQB-223会导致细胞活力和增殖受到抑制，其水平与MCF-7相当。值得注意的是，与MCF-7相比，MCF-7-Dox(R)细胞中P-糖蛋白外排泵的表达升高。
总之，这些结果表明LQB-223在敏感和耐药的乳腺癌细胞中介导细胞毒性作用，同时对非肿瘤性细胞呈现低毒性。这种新化合物可能代表了一种诱导乳腺癌细胞尤其是化疗耐药细胞毒性的潜在策略。
