Targeting cell cycle by β-carboline alkaloids in vitro: Novel therapeutic prospects for the treatment of cancer

Ahmad, Imad; Fakhri, Sajad; Khan, Haroon; Jeandet, Philippe; Aschner, Michael; Yu, Zhi Ling

doi:10.1016/j.cbi.2020.109229

Cited by 44 publications

(33 citation statements)

References 102 publications

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“…The aforementioned kinase complexes can phosphorylate RB1 together to release E2F to mediate the transition to the S phase ( 41 ). As demonstrated by Ahmad et al , β-carboline alkaloids that inhibit G0/G1 transition in cancer cells are believed to inhibit cyclin D1/D3 and reduce CDK4, CDK6, and cyclin E expression in HeLa cells ( 42 ). Similarly, our study revealed that DC induced apoptosis by reducing the expression of complex CDK4/6-cyclin D3 protein, thereby inhibiting the expression of RB phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways

Hsieh

Chuang

et al. 2021

Oncol Rep

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Nasopharyngeal carcinoma (NPC) is an indicator disease in Asia due to its unique geographical and ethnic distribution. Dehydrocrenatidine (DC) is a β-carboline alkaloid abundantly present in Picrasma quassioides (D. Don) Benn, a deciduous shrub or small tree native to temperate regions of southern Asia, and β-carboline alkaloids play anti-inflammatory and antiproliferative roles in various cancers. However, the mechanism and function of DC in human NPC cells remain only partially explored. The present study aimed to examine the cytotoxicity and biochemical role of DC in human NPC cells. The MTT method, cell cycle analysis, DAPI determination, Annexin V/PI double staining, and mitochondrial membrane potential examination were performed to evaluate the effects of DC treatment on human NPC cell lines. In addition, western blotting analysis was used to explore the effect of DC on apoptosis and signaling pathways in related proteins. The analysis results confirmed that DC significantly reduced the viability of NPC cell lines in a dose- and time-dependent manner and induced apoptosis through internal and external apoptotic pathways (including cell cycle arrest, altered mitochondrial membrane potential, and activated death receptors). Western blot analysis illustrated that DC's effect on related proteins in the mitogen-activated protein kinase pathway can induce apoptosis by enhancing ERK phosphorylation and inhibiting Janus kinase (JNK) phosphorylation. Notably, DC induced apoptosis by affecting the phosphorylation of JNK and ERK, and DC and inhibitors (SP600125 and U0126) in combination restored the overexpression of p-JNK and p-ERK. To date, this is the first study to confirm the apoptosis pathway induced by DC phosphorylation of p-JNK and p-REK in human NPC. On the basis of evidence obtained from this study, DC targeting the inhibition of NPC cell lines may be a promising future strategy for NPC treatment.

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Section: Discussionmentioning

confidence: 99%

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways

Hsieh

Chuang

et al. 2021

Oncol Rep

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“…To delve into the mechanism by which compounds 1-3 act against T. gondii tachyzoites, the progression of parasite cell cycle in the presence of the studied compounds was evaluated, since different βCs have proven to induce cell death through arresting cell cycle at different phases or transitions between them, in different cancer cell lines, yeast (Ahmad et al, 2020), and parasites (Di Giorgio et al, 2004). According to our results, 2 and 3 produced an increase of tachyzoite population in S/M phases, which agree with reported data for related compounds.…”

Section: Discussionmentioning

confidence: 99%

In vitro Effect of Harmine Alkaloid and Its N-Methyl Derivatives Against Toxoplasma gondii

et al. 2021

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Toxoplasmosis is one of the most prevalent and neglected zoonotic global diseases caused by Toxoplasma gondii. The current pharmacological treatments show clinical limitations, and therefore, the search for new drugs is an urgent need in order to eradicate this infection. Due to their intrinsic biological activities, β-carboline (βC) alkaloids might represent a good alternative that deserves further investigations. In this context, the in vitro anti-T. gondii activity of three βCs, harmine (1), 2-methyl-harminium (2), and 9-methyl-harmine (3), was evaluated herein. Briefly, the three alkaloids exerted direct effects on the parasite invasion and/or replication capability. Replication rates of intracellular treated tachyzoites were also affected in a dose-dependent manner, at noncytotoxic concentrations for host cells. Additionally, cell cycle analysis revealed that both methyl-derivatives 2 and 3 induce parasite arrest in S/M phases. Compound 3 showed the highest irreversible parasite growth inhibition, with a half maximal inhibitory concentration (IC50) value of 1.8 ± 0.2 μM and a selectivity index (SI) of 17.2 at 4 days post infection. Due to high replication rates, tachyzoites are frequently subjected to DNA double-strand breaks (DSBs). This highly toxic lesion triggers a series of DNA damage response reactions, starting with a kinase cascade that phosphorylates a large number of substrates, including the histone H2A.X to lead the early DSB marker γH2A.X. Western blot studies showed that basal expression of γH2A.X was reduced in the presence of 3. Interestingly, the typical increase in γH2A.X levels produced by camptothecin (CPT), a drug that generates DSB, was not observed when CPT was co-administered with 3. These findings suggest that 3 might disrupt Toxoplasma DNA damage response.

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“…Its imbalance would be the critical determinants of cancers [ 16 ]. Targeting the cell cycle, some medicines such as β-carboline alkaloids [ 17 ], abemaciclib [ 18 ], paclitaxel [ 19 ] et al, had presented significant therapeutic prospects in cancers. Moreover, some potential anticancer agents including diosmetin [ 20 ] and anethole [ 21 ] could also inhibit PCa cell proliferation mainly through arresting cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Carcinogenic effect of adenylosuccinate lyase (ADSL) in prostate cancer development and progression through the cell cycle pathway

Liao

Song

et al. 2021

Cancer Cell Int

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Background Prostate cancer (PCa) is still a serious male malignant disease across the world. However, no exact pathogenesis had been explained. Although adenylosuccinate lyase (ADSL) gene was identified to be important in PCa early in 1987, its comprehensive functions for PCa have not been presented. Methods The cBioPortal for Cancer Genomics, Oncomine and GEO database were retrieved to investigate the associations between of the ADSL gene and PCa. Then, the PC-3, DU145 and C4-2B cell lines were applied in vitro experiments. RNA sequencing and further western blot (WB) were applied to explore the potential mechanisms of ADSL gene in PCa. Results Based on PCa clinical datasets, we firstly found ADSL gene highly expressed in PCa tissues. Moreover, its transcript level increased in the metastatic PCa further. Elevated ADSL gene expression indicated a poor prognosis of PCa. While inhibiting the expression of ADSL with siRNA, the ability of cell proliferation and migration all declined markedly, with increased cell apoptosis inversely. Most of cells were blocked in the G0/G1 phase. Additionally, RNA sequencing also discovered the inactivity of cell cycle pathway after ADSL knockdown, which had also confirmed on the proteins levels. Conclusions Our study identified the ADSL as an oncogene of PCa through regulating the cell cycle pathway firstly, with explicit cell and clinical phenotypes. Further mechanisms were needed to confirm its carcinogenic effect.

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Targeting cell cycle by β-carboline alkaloids in vitro: Novel therapeutic prospects for the treatment of cancer

Cited by 44 publications

References 102 publications

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways

Dehydrocrenatidine extracted from Picrasma quassioides induces the apoptosis of nasopharyngeal carcinoma cells through the JNK and ERK signaling pathways

In vitro Effect of Harmine Alkaloid and Its N-Methyl Derivatives Against Toxoplasma gondii

Carcinogenic effect of adenylosuccinate lyase (ADSL) in prostate cancer development and progression through the cell cycle pathway

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