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

Ankith Sherapura; B M Siddesh; Vikas H Malojirao; Prabhu Thirusangu; B R Vijay Avin; N Suchetha Kumari; Y L Ramachandra; B T Prabhakar

doi:10.1016/j.phymed.2023.154981

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

Phytomedicine. 2023 Oct:119:154981. doi: 10.1016/j.phymed.2023.154981. Epub 2023 Jul 18.

Authors

Ankith Sherapura¹, B M Siddesh¹, Vikas H Malojirao², Prabhu Thirusangu³, B R Vijay Avin⁴, N Suchetha Kumari⁵, Y L Ramachandra⁶, B T Prabhakar⁷

Affiliations

¹ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India.
² Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India; Division for DNA Repair Research, Department of Neurosurgery, Centre for Neuroregeneration, Houston Methodist, Fannin Street, Houston, TX, USA.
³ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India; Department of Experidmental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India; Department of Pharmacology and Centre for Lung and Vascular Biology, University of Illinois at Chicago, Chicago, 60612, USA.
⁵ Department of Biochemistry, K.S. Hegde Medical College, Nitte University, Mangalore, India.
⁶ Postgraduate Department of Studies and Research in Biotechnology, Kuvempu University, Shankaraghatta, 577 451, Karnataka, India.
⁷ Molecular Biomedicine Laboratory, Postgraduate Department of Studies and Research in Biotechnology, Sahyadri Science College, Kuvempu University, Shivamogga, 577203, Karnataka, India. Electronic address: pbtssc@gmail.com.

PMID: 37531902
DOI: 10.1016/j.phymed.2023.154981

Abstract

Purpose: 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.

Background: 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.

Methods: 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.

Results: The results postulates, inhibition of hypoxia driven DDR proteins pATM^ser1981/pHIF-1α^ser696 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 CONCLUSION: 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.

Keywords: ATM/HIF; Anti-angiogenesis; DDR; Lung cancer; Solanidine; TME.

MeSH terms

Adenocarcinoma of Lung* / drug therapy
Alkaloids* / pharmacology
Animals
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Hypoxia / drug therapy
Hypoxia-Inducible Factor 1, alpha Subunit
Lung Neoplasms* / drug therapy
Neovascularization, Pathologic / drug therapy
Phosphorylation
Rats
Tumor Microenvironment

Substances

solanidine
Antineoplastic Agents
Alkaloids
Hypoxia-Inducible Factor 1, alpha Subunit