The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells

Priyadarsini, Ramamurthi Vidya; Ramalingam, Murugan; Sripriya, P.; Karunagaran, Devarajan; Nagini, Siddavaram

doi:10.3109/10715761003692503

Cited by 120 publications

(117 citation statements)

References 36 publications

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“…JNK is known to interact with, phosphorylate, and increase the stability of the cell-cycle regulator, p21 WAF1/CIP1 (43). Thus, ERK and JNK are signaling elements in several types of cells through which quercetin may regulate cell growth (44,45). We herein observed that quercetin exposure induced an increase in ERK1/2 and JNK phosphorylation in P39 cells and in P39 xenografts.…”

Section: Discussionsupporting

confidence: 51%

Multitarget Effects of Quercetin in Leukemia

Maso

Calgarotto

Franchi

et al. 2014

Cancer Prevention Research

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This study proposes to investigate quercetin antitumor efficacy in vitro and in vivo, using the P39 cell line as a model. The experimental design comprised leukemic cells or xenografts of P39 cells, treated in vitro or in vivo, respectively, with quercetin; apoptosis, cell-cycle and autophagy activation were then evaluated. Quercetin caused pronounced apoptosis in P39 leukemia cells, followed by Bcl-2, Bcl-xL, Mcl-1 downregulation, Bax upregulation, and mitochondrial translocation, triggering cytochrome c release and caspases activation. Quercetin also induced the expression of FasL protein. Furthermore, our results demonstrated an antioxidant activity of quercetin. Quercetin treatment resulted in an increased cell arrest in G 1 phase of the cell cycle, with pronounced decrease in CDK2, CDK6, cyclin D, cyclin E, and cyclin A proteins, decreased Rb phosphorylation and increased p21 and p27 expression. Quercetin induced autophagosome formation in the P39 cell line. Autophagy inhibition induced by quercetin with chloroquine triggered apoptosis but did not alter quercetin modulation in the G 1 phase. P39 cell treatment with a combination of quercetin and selective inhibitors of ERK1/2 and/or JNK (PD184352 or SP600125, respectively), significantly decreased cells in G 1 phase, this treatment, however, did not change the apoptotic cell number. Furthermore, in vivo administration of quercetin significantly reduced tumor volume in P39 xenografts and confirmed in vitro results regarding apoptosis, autophagy, and cell-cycle arrest. The antitumor activity of quercetin both in vitro and in vivo revealed in this study, point to quercetin as an attractive antitumor agent for hematologic malignancies. Cancer Prev Res; 7(12); 1240-50. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 51%

Multitarget Effects of Quercetin in Leukemia

Maso

Calgarotto

Franchi

et al. 2014

Cancer Prevention Research

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“…This was accompanied by the induction of cellular apoptosis [25]. Similarly, nimbolide was shown to induce apoptosis in human osteocarcinoma [26], Waldenstrom macroglobulinemia (WM) [11], human cervical cancer [27], and hepatocarcinoma cells [28]. Additionally, an in vitro study further indicated that nimbolide was able to combat metastasis and angiogenesis of cancer cells [29].…”

Section: Anti-cancer Activitiesmentioning

confidence: 99%

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

et al. 2016

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Nimbolide is one of the main components in the leaf extract of Azadirachta indica (A. indica). Accumulating evidence from various in vitro and in vivo studies indicates that nimbolide possesses potent anticancer activity against several types of cancer and also shows potential chemopreventive activity in animal models. The main mechanisms of action of nimbolide include anti-proliferation, induction of apoptosis, inhibition of metastasis and angiogenesis, and modulation of carcinogen-metabolizing enzymes. Although multiple pharmacodynamic (PD) studies have been carried out, nimbolide is still at the infant stage in the drug development pipeline due to the lack of systematic pharmacokinetic (PK) studies and long-term toxicological studies. Preclinical PK and toxicological studies are vital in determining the dosage range to support the safety of nimbolide for first-in-human clinical trials. In this review, we will provide a comprehensive summary for the current status of nimbolide as an anticancer and chemopreventive lead compound, and highlight the importance of systematic preclinical PK and toxicological studies in accelerating the process of application of nimbolide as a therapeutic agent against various malignancies.

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“…This limonoid has been shown to possess numerous biological activities such as antifeedant (21), antimalarial (22), antimicrobial (23), and anticancer (19, 20, 24–30) activities. The limonoid exhibits antiproliferative activity in a wide variety of tumor cells, including neuroblastoma, osteosarcoma, choriocarcinoma (31), cervical cancer (32), leukemia, and melanoma (29) cells.…”

Section: Introductionmentioning

confidence: 99%

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

Gupta

Prasad

Sethumadhavan

et al. 2013

Clinical Cancer Research

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Purpose Extensive research over the past decade has revealed that the proinflammatory microenvironment plays a critical role in the development of colorectal cancer (CRC). Whether nimbolide, a limonoid triterpene, can inhibit the growth of CRC was investigated in the present study. Experimental Design The effect of nimbolide on proliferation of CRC cell lines was examined by MTT assay, apoptosis by caspase activation and poly-ADP ribose polymerase cleavage, nuclear factor-kappa B (NF-kB) activation by DNA-binding assay, and protein expression by Western blotting. The effect of nimbolide on the tumor growth in vivo was examined in CRC xenografts in a nude mouse model. Results Nimbolide inhibited proliferation, induced apoptosis, and suppressed NF-κB activation and NF-κB–regulated tumorigenic proteins in CRC cells. The suppression of NF-κB activation by nimbolide was caused by sequential inhibition of IκB kinase (IKK) activation, IκBα phosphorylation, and p65 nuclear translocation. Furthermore, the effect of nimbolide on IKK activity was found to be direct. In vivo, nimbolide (at 5 and 20 mg/kg body weight), injected intraperitoneally after tumor inoculation, significantly decreased the volume of CRC xenografts. The limonoid-treated xenografts exhibited significant down-regulation in the expression of proteins involved in tumor cell survival (Bcl-2, Bcl-xL, c-IAP-1, survivin, Mcl-1), proliferation (c-Myc, cyclin D1), invasion (MMP-9, ICAM-1), metastasis (CXCR4), and angiogenesis (VEGF). The limonoid was found to be bioavailable in the blood plasma and tumor tissues of treated mice. Conclusions Our studies provide evidence that nimbolide can suppress the growth of human CRC through modulation of the proinflammatory microenvironment.

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The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells

Cited by 120 publications

References 36 publications

Multitarget Effects of Quercetin in Leukemia

Multitarget Effects of Quercetin in Leukemia

Anticancer properties of nimbolide and pharmacokinetic considerations to accelerate its development

Nimbolide, a Limonoid Triterpene, Inhibits Growth of Human Colorectal Cancer Xenografts by Suppressing the Proinflammatory Microenvironment

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