根据国家公共卫生研究所,前列腺癌(PCa)是墨西哥男性癌症死亡的主要原因,与侵略性高度相关,抵抗治疗,和转移性扩散(Bharti等人。,2019)由缺氧诱导因子1(HIF-1α)的激活介导。本研究的目的是评估HIF-1α激活在人前列腺腺癌细胞系LNCaP的放射生物学反应中的参与,用数学模型描述现象。在不同的暴露条件下形成四组,包括用CoCl2处理的低氧细胞(300μM,22小时),有或没有缺氧诱导因子抑制剂(在用CoCl2孵育18小时后,在完成22小时的孵育期前,加入150nMchetomin4小时)。将它们暴露于剂量范围为2至10Gy的60Co源以获得拟合到数学模型的存活曲线。CoCl2或chetomin处理不影响照射后保持不变的LNCaP细胞的活力。CoCl2诱导的缺氧降低了LNCaP的生存能力,和阻塞HIF-1α信号与chetomine产生轻微的辐射防护作用。正如其他人报告的那样,由HIF-1α激活诱导的遗传重编程充当选择具有更具攻击性行为的细胞的内在因子(Pressley等人。,2017),而切托明由于其清除剂特性而保护细胞免于死亡。有趣的是,用chetomin处理诱导缺氧的细胞(用CoCl2激活HIF-1)可显著降低LNCaP细胞的辐射抗性,证明同时使用切托明和γ辐射是治疗缺氧前列腺癌的有效选择。在分子水平上,我们建议HIF-1α施加的选择力取决于辐射产生的自由基。提出的数学模型表明,作为辐射剂量函数的细胞存活率变化率与两个函数的乘积成正比,一种描述细胞死亡,另一种描述自然或人工对辐射的抵抗力。
According to the National Institute of Public Health, prostate cancer (PCa) is the leading cause of cancer death in Mexican men, highly associated with aggressiveness, resistance to treatment, and metastatic spread (Bharti et al., 2019) mediated by activation of the hypoxia-inducible factor 1 (HIF-1α). The objective of the present study was to evaluate the participation of HIF-1α activation in the radiobiological response of the human prostate adenocarcinoma cell line LNCaP, describing the phenomena with a mathematical model. Four groups were formed under different exposure conditions, including hypoxic cells treated with CoCl2 (300 μM for 22 h) with or without hypoxia-inducible factor inhibitor (150 nM chetomin for 4 h added after an incubation period of 18 h with CoCl2, just before completing the incubation period of 22 h). They were exposed to a source of 60Co in a dose range between 2 and 10 Gy to obtain survival curves that are fitted to a mathematical model. CoCl2 or chetomin treatments do not affect the viability of LNCaP cells that remained unchanged after irradiation. CoCl2 induced hypoxia reduces the survivability of LNCaP, and obstruction of HIF-1α signaling with chetomine produces a slight radioprotective effect. As others report, the genetic reprogramming induced by HIF-1α activation acts as an intrinsic agent that selects cells with more aggressive behavior (Pressley et al., 2017), while chetomin protects cells from death due to its scavenger properties. Interestingly, treatment with chetomin of cells induced to hypoxia (HIF-1 activation with CoCl2) produces a significant reduction in the radioresistance of LNCaP cells, demonstrating that the simultaneous use of chetomin and gamma radiation is an effective option for the treatment of hypoxic prostate cancer. At the molecular level, we suggest that the selective force exerted by HIF-1α depends on the production of free radicals by radiation. The proposed mathematical model showed that the rate of change in cell survival as a function of radiation dose is proportional to the product of two functions, one that describes cell death and the other that describes natural or artificial resistance to radiation.