Effects of betulinic acid alone and in combination with irradiation in human melanoma cells
Effects of betulinic acid alone and in combination with irradiation in human melanoma cells
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DOI：
10.1046/j.1523-1747.2000.00972.x
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发表时间：
2000-05-01
影响因子：
6.5
通讯作者：
Kodym, R
中科院分区：
文献类型：
--
作者：
Selzer, E;Pimentel, E;Kodym, R
最近，白桦脂酸被证实是一种高度选择性的人黑色素瘤生长抑制剂，并被报道诱导黑色素瘤细胞凋亡。我们在一组已建立的人类黑色素瘤细胞系中以及在正常的人类黑素细胞中，研究了这种化合物单独和与电离辐射联合的生长抑制特性。白桦酸强烈而持续地抑制所有被研究的人黑色素瘤细胞系的生长和集落形成能力。在集落形成实验中，白桦酸与电离辐射联合作用对细胞生长的抑制作用是相加的。白桦酸还诱导人黑色素瘤细胞的凋亡，Annexin V结合和出现具有凋亡形态的细胞证明了这一点。白桦酸的生长抑制作用在人类黑色素瘤细胞系中比在正常的人类黑素细胞中更明显。值得注意的是，尽管白桦脂酸诱导了细胞凋亡，但对白桦酸处理的细胞中的Bcl2家族成员的表达分析显示，抗凋亡蛋白Mcl-1的表达被诱导了。此外，白桦酸的抗增殖作用似乎不依赖于P53的状态。白桦酸的性质使其成为一种有趣的候选药物，不仅是一种单一的药物，而且与放射治疗相结合。我们的结论是，生长抑制与辐射的严格相加模式表明，这两种治疗模式可能通过诱导不同的细胞死亡途径或通过影响不同的靶细胞群来发挥作用。
Recently, betulinic acid was identified as a highly selective inhibitor of human melanoma growth and was reported to induce apoptosis in these cells. We have investigated the growth-inhibitory properties of this compound alone and in combination with ionizing radiation in a panel of established human melanoma cell lines as well as in normal human melanocytes. Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated. In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays. Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology. The growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes. Notably, despite the induction of apoptosis, analysis of the expression of Bcl-2 family members in betulinic-acid-treated cells revealed that expression of the anti-apoptotic protein Mcl-1 was induced. Furthermore, the antiproliferative action of betulinic acid seemed to be independent of the p53 status. The properties of betulinic acid make it an interesting candidate, not only as a single agent but also in combination with radiotherapy. We conclude that the strictly additive mode of growth inhibition in combination with irradiation suggests that the two treatment modalities may function by inducing different cell death pathways or by affecting different target cell populations.