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The tumor antagonistic steroidal alkaloid Solanidine prompts the intrinsic suicidal signal mediated DFF-40 nuclear import and nucleosomal disruption.

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.

journal_name

Life Sci

journal_title

Life sciences

authors

Malojirao VH,Vigneshwaran V,Thirusangu P,Mahmood R,Prabhakar BT

doi

10.1016/j.lfs.2018.03.015

subject

Has Abstract

pub_date

2018-04-15 00:00:00

pages

139-150

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(18)30121-8

journal_volume

199

pub_type

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The tumor antagonistic steroidal alkaloid Solanidine prompts the intrinsic suicidal signal mediated DFF-40 nuclear import and nucleosomal disruption.