Cytotoxicity and cell cycle arrest induced by andrographolide lead to programmed cell death of MDA-MB-231 breast cancer cell line.
Cytotoxicity and cell cycle arrest induced by andrographolide lead to programmed cell death of MDA-MB-231 breast cancer cell line.
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穿心莲内酯诱导的细胞毒性和细胞周期停滞导致 MDA-MB-231 乳腺癌细胞系的程序性细胞死亡。
DOI：
10.1186/s12929-016-0257-0
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发表时间：
2016-04-16
影响因子：
11
通讯作者：
Mukherjee SK
中科院分区：
文献类型：
--
作者：
Banerjee M;Chattopadhyay S;Choudhuri T;Bera R;Kumar S;Chakraborty B;Mukherjee SK
在全球女性中遇到的恶性肿瘤中，乳腺癌被认为是日益严重的威胁生命的问题。由于耐药性和各种副作用，传统疗法远远不能令人满意，因此，人们强调从天然来源寻找副作用较小的补充/替代药物。穿心莲是一种常见于亚洲国家的东方传统中草药，具有悠久的治疗多种疾病的历史，如呼吸道感染、发热、细菌性痢疾、腹泻、炎症等。该植物的提取物具有广泛的治疗作用，如抗细菌、抗疟疾、抗病毒和抗癌特性。穿心莲内酯是一种二萜内酯，是该植物的主要活性成分。本研究报道了穿心莲内酯诱导高增殖、侵袭性乳腺癌细胞MDA-MB-231的凋亡及其可能的机制。此外，还研究了穿心莲内酯静脉和口服给药后在小鼠体内的药代动力学特性。穿心莲内酯对MDA-MB-231乳腺癌细胞的增殖抑制作用呈时间和浓度依赖性，但对正常乳腺上皮细胞MCF-10A无明显影响。作用36h后，S期细胞数和G2/M期细胞数均明显增加。观察到活性氧(ROS)的产生增加，同时线粒体膜电位(MMP)降低，磷脂酰丝氨酸外化。Annexin V流式细胞仪检测显示，随着穿心莲内酯作用时间的延长，细胞凋亡数增加。半胱氨酸天冬氨酸氨基转移酶-3和半胱氨酸天冬氨酸氨基转移酶-9被激活。穿心莲内酯作用后，Bax和APAF-1的表达明显增加，而Bcl2和Bclxl的表达明显降低。穿心莲内酯口服后的生物利用度为9.27 ± 1.69%，Cmax为0.73 ± 0.17μ /L，Tmax为0.42 ± 0.14 h。静脉和口服AG的半衰期(t1/2)分别为1.86 ± 0.21和3.30 ± 0.35h。这项研究表明，穿心莲内酯可能是一种可能的人类乳腺癌的化学预防/化疗药物。本文的在线版本(doi：10.1186/s12929-0160257-0)包含补充材料，授权用户可以使用。
Breast cancer is considered as an increasing major life-threatening concern among the malignancies encountered globally in females. Traditional therapy is far from satisfactory due to drug resistance and various side effects, thus a search for complementary/alternative medicines from natural sources with lesser side effects is being emphasized. Andrographis paniculata, an oriental, traditional medicinal herb commonly available in Asian countries, has a long history of treating a variety of diseases, such as respiratory infection, fever, bacterial dysentery, diarrhea, inflammation etc. Extracts of this plant showed a wide spectrum of therapeutic effects, such as anti-bacterial, anti-malarial, anti-viral and anti-carcinogenic properties. Andrographolide, a diterpenoid lactone, is the major active component of this plant. This study reports on andrographolide induced apoptosis and its possible mechanism in highly proliferative, invasive breast cancer cells, MDA-MB-231 lacking a functional p53 and estrogen receptor (ER). Furthermore, the pharmacokinetic properties of andrographolide have also been studied in mice following intravenous and oral administration. Andrographolide showed a time- and concentration- dependent inhibitory effect on MDA-MB-231 breast cancer cell proliferation, but the treatment did not affect normal breast epithelial cells, MCF-10A (>80 %). The number of cells in S as well as G2/M phase was increased after 36 h of treatment. Elevated reactive oxygen species (ROS) production with concomitant decrease in Mitochondrial Membrane Potential (MMP) and externalization of phosphatidyl serine were observed. Flow cytometry with Annexin V revealed that the population of apoptotic cells increased with prolonged exposure to andrographolide. Activation of caspase-3 and caspase-9 were also noted. Bax and Apaf-1 expression were notably increased with decreased Bcl-2 and Bcl-xL expression in andrographolide-treated cells. Pharmacokinetic study with andrographolide showed the bioavailability of 9.27 ± 1.69 % with a Cmax, of 0.73 ± 0.17 μmol/L and Tmax of 0.42 ± 0.14 h following oral administration. AG showed rapid clearance and moderate terminal half lives (T1/2) of 1.86 ± 0.21 and 3.30 ± 0.35 h following IV and oral administration respectively. This investigation indicates that andrographolide might be useful as a possible chemopreventive/chemotherapeutic agent for human breast cancers. The online version of this article (doi:10.1186/s12929-016-0257-0) contains supplementary material, which is available to authorized users.