Journal of Photochemistry & Photobiology B Biology, 2010, 98(1):25-34.

Down-regulation of Bcl-2 and Akt induced by combination of photoactivated hypericin and genistein in human breast cancer cells

Peter Ferenc, Peter Fedorocko, et al

Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 040 01 Košice, Slovakia

Presented experiment considers combination of genistein and photodynamic therapy with hypericin with a view to achieve higher therapeutic outcome in human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231, both identified in our conditions as photodynamic therapy resistant. Since genistein is known to suppress Bcl-2 expression, we predicted that photodynamic therapy with hypericin might benefit from mutual therapeutic combination. In line with our expectations, combined treatment led to down-regulation of Bcl-2 and up-regulation of Bax in both cell lines as well as to suppression of Akt and Erk1/2 phosphorylation induced by photoactivated hypericin in MCF-7 cells. Although Akt and Erk1/2 phosphorylation was not stimulated by photodynamic therapy with hypericin in MDA-MB-231 cells, it was effectively suppressed in combination. Variations in cell death signaling favoring apoptosis were indeed accompanied by cell cycle arrest in G(2)/M-phase, activation of caspase-7, PARP cleavage and increased occurrence of cells with apoptotic morphology of nucleus. All these events corresponded with suppression of proliferation and significantly lowered clonogenic ability of treated cells. In conclusion, our results indicate that pre-treatment with tyrosine kinase inhibitor genistein may significantly improve the effectiveness of photodynamic therapy with hypericin in MCF-7 and MDA-MB-231 breast cancer cells.

瑞士《光化学与光生物学杂志，B辑：生物学》，2010年1月

在人体乳腺癌细胞中光活化的金丝桃素和染料木黄酮的联合诱导Bcl-2 与 Akt 的向下调节

彼得  费伦茨，彼得 菲德瑞克等

斯洛伐克普雷绍夫帕沃尔约瑟夫大学生物学和生态学研究所

目前的实验认为在人体乳腺癌腺癌细胞 MCF-7 和MDA-MB-231中，金雀异黄素和金丝桃素光动力疗法的联合疗法可以实现更高的治疗成果，并且在我们的条件下两者被确认作为光动力治疗的耐药剂。因为金雀异黄素能够抑制 Bcl-2 表达，我们预测其与金丝桃素的光动力疗法联合治疗可能会相互受益。按照我们的期望，联合治疗在两个细胞中都会导致Bcl-2的下调和Bax的上调，并且在MCF-7细胞中光活化的金丝桃素会诱导抑制 Akt 和 Erk1/2 的磷酸化。虽然在 MDA-MB-231 细胞中Akt 和 Erk1/2 的磷酸化没有受到金丝桃素光动力疗法的刺激，联合疗法可以有效地抑制。细胞死亡信号顺利凋亡的变化的确伴随细胞周期在 G 2/M 期的阻滞，半胱氨酸蛋白酶-7的活化、 PARP 卵裂以及细胞核凋亡形态学发生率的增强。以上所有增殖了抑制细胞增殖并且明显降低了治疗细胞的克隆源性能力。总之，我们的研究结果表明，用酪氨酸激酶抑制剂金雀异黄素提前治疗可能大大增强金丝桃素光动力疗法对乳腺癌细胞MCF-7 和 MDA- MB-231的效用。