Ravid A, Rocker D, Machlenkin A, Rotem C, Hochman A, Kessler-Icekson G, Liberman U A, Koren R
The Basil and Gerald Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel.
Cancer Res. 1999 Feb 15;59(4):862-7.
1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
1,25 - 二羟基维生素D3（1,25(OH)2D3）是维生素D的激素形式，在体内和体外均具有抗癌活性。阿霉素主要通过两种机制对肿瘤细胞发挥细胞毒性作用：（a）产生活性氧（ROS）；（b）抑制拓扑异构酶II。我们研究了1,25(OH)2D3与阿霉素对MCF - 7乳腺癌细胞的联合细胞毒性作用。用1,25(OH)2D3预处理可增强阿霉素的细胞毒性。用1,25(OH)2D3（10 nM）预处理72小时，然后用1微克/毫升阿霉素处理24小时，平均增强效果为74±9%（平均值±标准误）。在这些实验条件下，单独的1,25(OH)2D3不影响细胞数量或活力。1,25(OH)2D3还增强了另一种产生活性氧的醌类物质甲萘醌的细胞毒性活性，但不影响拓扑异构酶抑制剂依托泊苷诱导的细胞毒性。抗氧化剂N - 乙酰半胱氨酸略微降低了阿霉素的细胞毒性活性，但对1,25(OH)2D3和阿霉素的联合作用具有显著的保护作用。这些结果表明，活性氧参与了1,25(OH)2D3与阿霉素之间的相互作用。1,25(OH)2D3还增加了大鼠心肌细胞原代培养物中阿霉素的细胞毒性。单独用1,25(OH)2D3处理MCF - 7细胞可显著降低细胞质抗氧化酶铜/锌超氧化物歧化酶的活性、蛋白质和mRNA水平，这表明该激素抑制其生物合成。细胞抗氧化能力的这种降低可能解释了1,25(OH)2D3与阿霉素之间的协同相互作用，也可能表明1,25(OH)2D3或其类似物与其他产生活性氧的抗癌治疗方式联合使用时疗效增加。
