Conofolidine: A Natural Plant Alkaloid That Causes Apoptosis and Senescence in Cancer Cells

Al-Hayali, Mohammed Zuhair; Nge, Choy-Eng; Lim, Kuan Hon; Collins, Hilary M.; Kam, Toh-Seok; Bradshaw, Tracey D.

Abstract

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine’s broad-spectrum anticancer activity together with that of three other bisindoles—conophylline, leucophyllidine, and bipleiophylline—against human-derived breast, colorectal, pancreatic, and lung carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (e.g., in MDA-MB-468 breast) or senescence (e.g., in HT-29 colorectal) in cancer cells. Annexin V-FITC/PI, caspase activation, and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Cell cycle perturbations were evident, comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed an induction of aberrant mitotic phenotypes-membrane blebbing, DNA-fragmentation with occasional multi-nucleation. DNA integrity assessment in HCT-116, MDA-MB-468, MIAPaCa-2, and HT-29 cells showed increased fluorescent γ-H2AX during the G1 cell cycle phase; γ-H2AX foci were validated in HCT-116 and MDA-MB-468 cells by confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by increased NQO1 expression. Collectively, we present conofolidine as a putative potent anticancer agent capable of inducing heterogeneous modes of cancerous cell death in vitro, encouraging further preclinical evaluations of this natural product.

Citation

Al-Hayali, M. Z., Nge, C.-E., Lim, K. H., Collins, H. M., Kam, T.-S., & Bradshaw, T. D. (2024). Conofolidine: A Natural Plant Alkaloid That Causes Apoptosis and Senescence in Cancer Cells. Molecules, 29(11), Article 2654. https://doi.org/10.3390/molecules29112654

• Journal Article Type: Article
• Acceptance Date: May 28, 2024
• Online Publication Date: Jun 4, 2024
• Publication Date: Jun 4, 2024
• Deposit Date: Jun 10, 2024
• Publicly Available Date: Jun 10, 2024
• Journal: Molecules
• Electronic ISSN: 1420-3049
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 29
• Issue: 11
• Article Number: 2654
• DOI: https://doi.org/10.3390/molecules29112654
• Keywords: conofolidine; bisindole alkaloids; carcinoma cell lines; cytotoxicity; apoptosis; senescence; ROS generation; γ-H2AX
• Public URL: https://nottingham-repository.worktribe.com/output/35735098
• Publisher URL: https://www.mdpi.com/1420-3049/29/11/2654