Alkaloid-rich fraction of Ervatamia coronaria sensitizes colorectal cancer through modulating AMPK and mTOR signalling pathways

Dutta, Naibedya and Pemmaraju, Deepak Bharadwaj and Rengan, Aravind Kumar and et al, . (2022) Alkaloid-rich fraction of Ervatamia coronaria sensitizes colorectal cancer through modulating AMPK and mTOR signalling pathways. Journal of Ethnopharmacology, 283. ISSN 0378-8741

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Abstract

Ethnopharmacological relevance: Ervatamia coronaria, a popular garden plant in India and some other parts of the world is known traditionally for its anti-inflammatory and anti-cancer properties. The molecular bases of these functions remain poorly understood. Aim of the study: Efficacies of the existing therapies for colorectal cancer (CRC) are limited by their life-threatening side effects and unaffordability. Therefore, identifying a safer, efficient, and affordable therapeutic is urgent. We studied the anti-CRC activity of an alkaloid-rich fraction of E. coronaria leaf extracts (AFE) and associated underlying mechanism. Materials and methods: Activity guided solvant fractionation was adopted to identify the activity in AFE. Different cell lines, and tumor grown in syngeneic mice were used to understand the anti-CRC effect. Methodologies such as LCMS, MTT, RT-qPCR, immunoblot, immunohistochemistry were employed to understand the molecular basis of its activity. Results: We showed that AFE, which carries about six major compounds, is highly toxic to colorectal cancer (CRC) cells. AFE induced cell cycle arrest at G1 phase and p21 and p27 genes, while those of CDK2, CDK-4, cyclin-D, and cyclin-E genes were downregulated in HCT116 cells. It predominantly induced apoptosis in HCT116p53+/+ cells while the HCT116p53-/- cells under the same treatment condition died by autophagy. Notably, AFE induced upregulation of AMPK phosphorylation, and inhibition of both of the mTOR complexes as indicated by inhibition of phosphorylation of S6K1, 4EBP1, and AKT. Furthermore, AFE inhibited mTOR-driven conversion of cells from reversible cell cycle arrest to senescence (geroconversion) as well as ERK activity. AFE activity was independent of ROS produced, and did not primarily target the cellular DNA or cytoskeleton. AFE also efficiently regressed CT26-derived solid tumor in Balb/c mice acting alone or in synergy with 5FU through inducing autophagy as a major mechanism of action as indicated by upregulation of Beclin 1 and phospho-AMPK, and inhibition of phospho-S6K1 levels in the tumor tissue lysates. Conclusion: AFE induced CRC death through activation of both apoptotic and autophagy pathways without affecting the normal cells. This study provided a logical basis for consideration of AFE in future therapy regimen to overcome the limitations associated with existing anti-CRC chemotherapy. © 2021 Elsevier B.V.

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IITH Creators:

IITH Creators	ORCiD
Rengan, Aravind Kumar	https://orcid.org/0000-0003-3994-6760

Item Type:

Article

Additional Information:

We thank Sibsankar Roy, Samit Adhya, Manikuntala Kundu, Gopal Chakrabarti for sharing antibodies. We thank Sanghamitra Raha, and Srabani Pal for their constant support. We thank Rahul L Gajbhiye for his help in LCMS analysis. ND is a recipient of ICMR SRF fellowship. DP was supported by funds from DBT . SG is a CSIR adhoc senior research fellow. We thank SERB, DBT and Bose Institute for financial support.

Uncontrolled Keywords:

Alkaloid fraction; Autophagy activator; Colorectal cancer; Ervatamia coronaria; mTOR inhibitor

Subjects:

Others > Medicine
Others > Pharmacy
Others > Cell Biology
Others > Cell Tissue Engineering
Others > Biomedical engineering
Others > Cellular biology

Divisions:

Department of Biomedical Engineering

Depositing User:

. LibTrainee 2021

Date Deposited:

14 Jul 2022 09:46

Last Modified:

14 Jul 2022 09:46