Nimbolide is a tetranortriterpenoid derived from the leaves and flowers of Azadirachta indica (Neem). It exhibits anticancer activity against a variety of cancers by modulating various crucial features, including cell proliferation, apoptosis, and invasion and metastasis. More importantly, the cytotoxic effect of nimbolide has also been observed against T cell lymphoma, but the underlying mechanisms are still unexplored. So far, no study has been conducted to observe the effect of nimbolide on cancer cell metabolism. Therefore, the present investigation was designed to explore the molecular mechanisms of the antitumor potential of nimbolide against T cell lymphoma, a neoplastic disorder of thymic origin. In addition, we also unraveled the anti-glycolytic activity of nimbolide against T lymphoma cells with possible molecular mechanisms. Our results showed the cytotoxic action of nimbolide against three different cell lines of T cell lymphoma, namely Dalton's lymphoma, HuT-78, and J6. Nimbolide-induced apoptosis in T lymphoma cells by altering the level of reactive oxygen species, p53, Bcl2, Bax, and cytochrome c, with subsequent cleavage of caspase 3. Remarkably, nimbolide inhibited the expression of hypoxia-inducible factor-1α, glucose transporter 3, hexokinase II, and pyruvate dehydrogenase kinase 1, which led to the suppression of glycolysis with concomitant activation of oxidative phosphorylation. Hence, the results of the present investigation demonstrate that nimbolide exerts tumoricidal activity against T lymphoma cells via augmentation of apoptosis and reversal of altered cell metabolism. Thus, the present study provides a new insight for the therapeutic utilization of nimbolide against T cell lymphoma.

中文翻译：

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Nimbolide 诱导 T 淋巴瘤细胞死亡：改变细胞凋亡和葡萄糖代谢的意义

Nimbolide 是一种来自印楝 (Neem) 叶和花的四降三萜类化合物。它通过调节各种关键特征，包括细胞增殖、凋亡、侵袭和转移，对多种癌症表现出抗癌活性。更重要的是，还观察到 nimbolide 对 T 细胞淋巴瘤的细胞毒性作用，但其潜在机制仍有待探索。到目前为止，还没有研究观察茚果内酯对癌细胞代谢的影响。因此，本研究旨在探索丁香内酯对 T 细胞淋巴瘤（一种胸腺来源的肿瘤性疾病）的抗肿瘤潜力的分子机制。此外，我们还通过可能的分子机制阐明了林果内酯对 T 淋巴瘤细胞的抗糖酵解活性。我们的研究结果表明，尼姆波内酯对三种不同的 T 细胞淋巴瘤细胞系，即道尔顿淋巴瘤、HuT-78 和 J6 具有细胞毒性作用。Nimbolide 通过改变活性氧、p53、Bcl2、Bax 和细胞色素 c 的水平，随后裂解 caspase 3 诱导 T 淋巴瘤细胞凋亡。 值得注意的是，nimbolide 抑制缺氧诱导因子-1α（葡萄糖转运蛋白）的表达3、己糖激酶 II 和丙酮酸脱氢酶激酶 1，导致糖酵解的抑制并伴随氧化磷酸化的激活。因此，本研究的结果表明，尼姆波内酯通过增加细胞凋亡和逆转改变的细胞代谢对 T 淋巴瘤细胞发挥杀肿瘤活性。因此，