Vikas H Malojirao1, V Vigneshwaran2, Prabhu Thirusangu1, Riaz Mahmood3, B T Prabhakar4. 1. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India. 2. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India; Department of Pharmacology, Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago 60612, USA. 3. Postgraduate Department of Studies and Research in Biotechnology & Bioinformatics, Kuvempu University, Shankaraghatta, Shivamogga 577203, Karnataka, India. 4. Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College (Autonomous), Kuvempu University, Shivamogga 577203, Karnataka, India. Electronic address: prabhakarbt1@kussc.org.
Abstract
Aim Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems. MAIN METHODS: Anti-proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin-V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In-vitro results were revalidated in EAC solid tumor and CAM xenograft model. KEY FINDINGS: Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S-G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl-2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase-3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF-40. Anti-carcinogenic aptitude was further confirmed by murine solid tumors and in-vivo CAM xenograft studies. SIGNIFICANCE: Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF-40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy.
Aim Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems. MAIN METHODS: Anti-proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin-V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In-vitro results were revalidated in EAC solid tumor and CAM xenograft model. KEY FINDINGS:Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S-G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl-2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase-3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF-40. Anti-carcinogenic aptitude was further confirmed by murine solid tumors and in-vivo CAM xenograft studies. SIGNIFICANCE: Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF-40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy.
Authors: Ankith Sherapura; Vikas H Malojirao; B S Sharath; Prabhu Thirusangu; Riaz Mahmood; N Suchetha Kumari; Shrinath M Baliga; Shaukath Ara Khanum; B T Prabhakar Journal: Pharmacol Rep Date: 2022-01-10 Impact factor: 3.024
Authors: Ankith Sherapura; Vikas H Malojirao; Prabhu Thirusangu; B S Sharath; Shivananda Kandagalla; V Vigneshwaran; Jurica Novak; Lakshmi Ranganatha; Y L Ramachandra; Shrinath M Baliga; Shaukath Ara Khanum; B T Prabhakar Journal: Apoptosis Date: 2021-11-27 Impact factor: 4.677