Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Japan.
Cancer. 2011 Jun 15;117(12):2735-46. doi: 10.1002/cncr.25711. Epub 2010 Dec 23.
Human T-cell leukemia is an aggressive malignancy of T lymphocytes. T-cell leukemia has a very poor prognosis, even with intensive chemotherapy, indicating the need for development of new drugs to treat the disease. Triterpenoid cucurbitacins have been shown to have antitumor activity, but the mechanism of this activity is not fully understood.
The effects of cucurbitacin D on the proliferation and apoptotic induction of T-cell leukemia cells using the Cell viability assay and Annexin V staining were evaluated. To investigate the mechanisms of apoptosis, antiapoptotic protein, NF-κB, and the proteasome activity of leukemia cells treated with cucurbitacin D were evaluated by Western blotting both in vitro and in vivo.
In this study, cucurbitacin D was found to inhibit proliferation and to induce apoptosis of T-cell leukemia cells. Constitutively activated NF-κB was inhibited by cucurbitacin D in the nucleus, which resulted in accumulation of NF-κB in the cytoplasm, leading to down-regulation of the expression of antiapoptotic proteins Bcl-xL and Bcl-2. Furthermore, cucurbitacin D induced the accumulation of inhibitor of NF-κB (IκB)α by inhibition of proteasome activity. Low doses of cucurbitacin D synergistically potentiated the antiproliferative effects of the histone deacetylase inhibitor VPA. Finally, the proapoptotic and proteasome inhibitory activities of cucurbitacin D also were demonstrated using SCID mice in an in vivo study.
Cucurbitacin D induced apoptosis through suppression of proteasome activity both in vitro and in vivo, making cucurbitacin D a promising candidate for clinical applications in the treatment of T-cell leukemia.
人类 T 细胞白血病是 T 淋巴细胞的侵袭性恶性肿瘤。T 细胞白血病的预后非常差，即使采用强化化疗，也表明需要开发新的药物来治疗这种疾病。三萜类葫芦素已被证明具有抗肿瘤活性，但这种活性的机制尚未完全了解。
采用细胞活力测定法和 Annexin V 染色法评估葫芦素 D 对 T 细胞白血病细胞增殖和凋亡诱导的影响。为了研究凋亡的机制，通过 Western 印迹法评估了葫芦素 D 在体外和体内对白血病细胞中抗凋亡蛋白、NF-κB 和蛋白酶体活性的影响。
本研究发现葫芦素 D 可抑制 T 细胞白血病细胞的增殖并诱导其凋亡。葫芦素 D 在细胞核中抑制了组成性激活的 NF-κB，导致 NF-κB 在细胞质中积累，从而下调抗凋亡蛋白 Bcl-xL 和 Bcl-2 的表达。此外，葫芦素 D 通过抑制蛋白酶体活性诱导 NF-κB 抑制剂（IκB）α 的积累。低剂量的葫芦素 D 与组蛋白去乙酰化酶抑制剂 VPA 协同增强了其抗增殖作用。最后，在体内研究中也证明了葫芦素 D 的促凋亡和蛋白酶体抑制活性。
葫芦素 D 通过抑制蛋白酶体活性在体外和体内诱导细胞凋亡，使葫芦素 D 成为治疗 T 细胞白血病的临床应用的有前途的候选药物。
