Doctorado en Farmacología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, México.
División de Inmunología, Centro de Investigación Biomédica de Occidente del IMSS, Sierra Mojada 800, Col. Independencia, CP 44340, Guadalajara, Jalisco, México.
BMC Urol. 2021 Mar 12;21(1):38. doi: 10.1186/s12894-021-00807-6.
Prostate cancer is one of the most frequently diagnosed types of cancers worldwide. In its initial period, the tumor is hormone-sensitive, but in advanced states, it evolves into a metastatic castration-resistant tumor. In this state, chemotherapy with taxanes such as Docetaxel (DTX) comprises the first line of treatment. However, the response is poor due to chemoresistance and toxicity. On the other hand, Pentoxifylline (PTX) is an unspecific inhibitor of phosphodiesterases; experimental, and clinically it has been described as sensitizing tumor cells to chemotherapy, increasing apoptosis and decreasing senescence. We study whether the PTX sensitizes prostate cancer cells to DTX for greater effectiveness.
PC3 human prostate cancer cells were treated in vitro at different doses and times with PTX, DTX, or their combination. Viability was determined by the WST-1 assay by spectrophotometry, cell cycle progression, apoptosis, generic caspase activation and senescence by flow cytometry, DNA fragmentation and caspases-3, -8, and -9 activity by ELISA.
We found that PTX in PC3 human prostate cancer cells induces significant apoptosis per se and increases that generated by DTX, while at the same time it reduces the senescence caused by the chemotherapy and increases caspases-3,-8, and -9 activity in PTX + DTX-treated cells. Both treatments blocked the PC3 cell in the G1 phase.
Our results show that PTX sensitizes prostate tumor cells to apoptosis induced by DTX. Taken together, the results support the concept of chemotherapy with rational molecular bases.
前列腺癌是全球最常见的癌症类型之一。在早期，肿瘤对激素敏感，但在晚期，它会发展为转移性去势抵抗性肿瘤。在这种状态下，用紫杉醇类药物（如多西他赛，DTX）进行化疗是一线治疗方法。然而，由于化疗耐药性和毒性，反应不佳。另一方面，己酮可可碱（PTX）是一种非特异性磷酸二酯酶抑制剂；实验和临床都描述它能使肿瘤细胞对化疗敏感，增加细胞凋亡，减少衰老。我们研究了 PTX 是否能使前列腺癌细胞对 DTX 更敏感，从而提高疗效。
在体外，用人前列腺癌细胞 PC3 用不同剂量和时间用 PTX、DTX 或它们的组合进行处理。用分光光度法通过 WST-1 测定法测定细胞活力，用流式细胞术测定细胞周期进展、凋亡、通用半胱天冬酶激活和衰老，用 ELISA 测定 DNA 片段化和半胱天冬酶-3、-8 和 -9 的活性。
我们发现 PTX 本身就能诱导人前列腺癌细胞 PC3 发生显著的凋亡，并增加 DTX 诱导的凋亡，同时降低化疗引起的衰老，并增加 PTX+DTX 处理细胞中的半胱天冬酶-3、-8 和 -9 的活性。两种处理都能使 PC3 细胞阻滞在 G1 期。
我们的结果表明，PTX 能使前列腺肿瘤细胞对 DTX 诱导的凋亡敏感。综上所述，这些结果支持了具有合理分子基础的化疗概念。
