Faculty of Science, Assam Down Town University, Panikhaiti, Guwahati, 781026, Assam, India; Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India.
Traditional and Modern Drug Discovery and Diseases Diagnosis Laboratory, Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, 781035, Assam, India; Department of Zoology, Gauhati University, Guwahati, 781014, Assam, India.
J Ethnopharmacol. 2024 Jan 30;319(Pt 2):117235. doi: 10.1016/j.jep.2023.117235. Epub 2023 Oct 5.
Mahanine (MH), a naturally occurring carbazole alkaloid, isolated from Ayurvedic medicinal plant Murraya koenigii (L.) Spreng, has been shown to have various pharmacological properties, including its inhibitory activity against different breast cancers (BC) subtypes.
While MH triggers apoptosis in BC cells regardless of subtype, the specific mechanism of MH action is not fully understood. In this study, we show the effect of MH in preventing BC progression by inducing apoptosis in relation to estrogen receptor-α (ERα) and cell cycle regulatory proteins.
To assess the pharmacological activity in various in vitro and in vivo tests, isolated and pure MH was used. To conclude the study, cutting edged molecular biology techniques including Western blot analysis, enzyme-linked immunosorbent assay (ELISA), molecular simulation study, and other related software analysis were employed.
MH demonstrated dose dependent cell viability against drug sensitive (MCF-7 and MDA-MB-231) and paclitaxel resistant (MCF-7TR and MDA-MB-231TR) BC cells. MH also exhibited synergistic activity with tamoxifen (TAM) against estrogen receptor positive (ER+) BC cells by inhibiting ERα expression in MCF-7 cells and N-Methyl-N-nitrosourea (MNU)-induced mammary tumor in a dose-dependent manner while having no effect on vinculin expression. In addition, MH inhibited cell cycle regulatory genes namely CDK1/CDK4/CDK6/CDC25A and neo-angiogenesis through downregulation of CD31/PECAMs in MCF-7, MDA-MB-231 cells and mammary tumors from MNU-induced rats. MH therapy has been shown to be significantly able to lower the serum leptin level and to be beneficial against the initiation of tumor development in SD rats for up to 12 weeks. Molecular modeling study revealed that MH has antagonized the effectiveness of several types of estrogen those bind to the ERα and has comparable binding efficacy to TAM.
Overall, the current investigation showed the ability of MH to modify cell cycle genes especially CDK4 and CDK6 might be responsible for its anticancer activity against different breast cancer subtypes. Additionally, this study will aid in advancing MH translational research to the clinical trial stage.
从印度阿育吠陀药用植物 Murraya koenigii（L.）Spreng 中分离得到的天然咔唑生物碱马汉宁（MH）已显示出多种药理学特性，包括对不同乳腺癌（BC）亚型的抑制活性。
虽然 MH 无论 BC 亚型如何都能触发细胞凋亡，但 MH 作用的具体机制尚不完全清楚。在这项研究中，我们通过诱导与雌激素受体-α（ERα）和细胞周期调节蛋白相关的细胞凋亡来显示 MH 在预防 BC 进展中的作用。
为了评估各种体外和体内试验中的药理学活性，使用了分离和纯 MH。为了得出研究结论，采用了尖端的分子生物学技术，包括 Western blot 分析、酶联免疫吸附测定（ELISA）、分子模拟研究和其他相关软件分析。
MH 对药物敏感（MCF-7 和 MDA-MB-231）和紫杉醇耐药（MCF-7TR 和 MDA-MB-231TR）BC 细胞的细胞活力表现出剂量依赖性。MH 还通过抑制 MCF-7 细胞中的 ERα 表达和 N-甲基-N-亚硝脲（MNU）诱导的乳腺肿瘤，与他莫昔芬（TAM）表现出协同活性，呈剂量依赖性，而对 vinculin 表达没有影响。此外，MH 通过下调 MCF-7、MDA-MB-231 细胞中的 CD31/PECAMs 和 MNU 诱导的大鼠乳腺肿瘤中的细胞周期调节基因，如 CDK1/CDK4/CDK6/CDC25A 和新生血管生成。MH 治疗已被证明能够显著降低血清瘦素水平，并有利于 SD 大鼠长达 12 周的肿瘤发生起始。分子建模研究表明，MH 拮抗了几种与 ERα 结合的雌激素的有效性，并且与 TAM 具有可比的结合效力。
总的来说，目前的研究表明，MH 改变细胞周期基因的能力，特别是 CDK4 和 CDK6，可能是其对不同乳腺癌亚型抗癌活性的原因。此外，这项研究将有助于推进 MH 转化研究进入临床试验阶段。
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