Steroidal alkaloid solanidine impedes hypoxia-driven ATM phosphorylation to switch on anti-angiogenesis in lung adenocarcinoma

• Published in: Phytomedicine (Stuttgart) Vol. 119; p. 154981
• Main Authors: Sherapura, Ankith, Siddesh, B.M., Malojirao, Vikas H., Thirusangu, Prabhu, Avin, B.R. Vijay, Kumari, N Suchetha, Ramachandra, Y.L., Prabhakar, B.T.
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.10.2023
• Subjects: Anti-angiogenesis; ATM/HIF; DDR; Lung cancer; Solanidine; TME; LLC; TNFα; Lung cancer; VEGF; DAPI 4; XRCC1; Solanidine; HIF-1α; HR; Chk2; TME; BER; ECM; MMP 2&9; ATM/HIF; DNA DSB; IL6; DDR; ATM; HRE; MVD; Anti-angiogenesis; ELISA
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2023.154981

•TME perseveres complex interwoven signaling nexus of inflammatory hypoxia and DDR pathways.•Hypoxia driven ATM/HIF-1α phosphorylation promotes tumor angiogenesis and apoptosis.•Antiproliferative molecule solanidine evaluated to target ATM/HIF-1α signaling.•Solanidine impedes pATM/pHIF-1α mediated anti-angiogenesis and induction of apoptosis.•Solanidine exhibited as novel multidimensional phytomedicine in targeting lung cancer. The declined oxygen tension in the cancer cell leads to the hypoxic adaptive response and favors establishment of tumor micro environment [TEM]. The complex TME consists of interwoven hypoxic HIF-1α and DNA damage repair ATM signaling. The ATM/HIF-1α phosphorylation switch on angiogenesis and abort apoptosis. Targeting this signaling nexus would be a novel therapeutic strategy for the treatment of cancer. Steroidal alkaloid solanidine is known for varied pharmacological role but with less molecular evidences. Our earlier findings on solanidine proven its anti-neoplastic activity by inducing apoptosis in lung cancer. In continued research, efforts have been made to establish the underlying molecular signaling in induction of DNA damage in prevailing hypoxic TME. The solanidine induced DNA damage was assessed trough alkali COMET assay; signaling nexus and gene expression profile analysis through IB, qRT-PCR, Gelatin Zymography, IHC, IF and ELISA. Pathophysiological modulations assessed through tube formation, migration, invasion assays. Anti-angiogenic studies through CAM, rat aorta, matrigel assays and corneal neovascularization assay. Anti-tumor activity through in-vivo DLA ascites tumor model and LLC model. The results postulates, inhibition of hypoxia driven DDR proteins pATMser1981/pHIF-1αser696 by solanidine induces anti-angiogenesis. Systematic study of both non-tumorigenic and tumorigenic models in-vitro as well as in-vivo experimental system revealed the angio-regression mediated anticancer effect in lung cancer. These effects are due to the impeded expression of angiogenic mediators such as VEGF, MMP2&9 and inflammatory cytokines IL6 and TNFα to induce pathophysiological changes The study establishes new role of solanidine by targeting ATM/HIF-1α signaling to induce anti-angiogenesis for the first time. The study highlights the potentiality of plant based phytomedicine solanidine which can targets the multiple hallmarks of cancer by targeting interwoven signaling crosstalk. Such an approach through solanidine necessary to counteract heterogeneous complexity of cancer which could be nearly translated into drug. [Display omitted]