癌细胞中氧张力下降导致缺氧适应性反应，并有利于肿瘤微环境（TEM）的形成。复杂的TME由交织的缺氧HIF-1α和DNA损伤修复ATM信号组成。ATM/HIF-1α磷酸化开关对血管生成和抑制凋亡起作用。靶向这种信号网络可能是治疗癌症的新策略。类固醇类生物碱溶菌酮的药理作用已知较多，但分子证据较少。我们早期的研究发现溶菌酮通过诱导肺癌细胞凋亡表现出抗肿瘤活性。在持续的研究中，我们努力确定在现有缺氧TME中引发DNA损伤的潜在分子信号。通过碱基COMET实验评估溶菌酮诱导的DNA损伤；通过IB、qRT-PCR、明胶酶解Zymography、免疫组化、免疫荧光和ELISA进行信号网络和基因表达谱分析。通过管形成、迁移、侵袭实验评估病理生理学调节。通过CAM、大鼠主动脉、基质凝胶和角膜新生血管化实验进行抗血管生成研究。通过体内DLA腹水瘤模型和LLC模型评估抗肿瘤活性。结果表明，溶菌酮通过抑制缺氧驱动的DDR蛋白pATMser1981/pHIF-1αser696诱导抗血管生成。通过体外和体内实验系统对非肿瘤和肿瘤模型进行系统研究，揭示了丝裂原抑制剂呈抗肿瘤效应的机制。这些效应是由于血管生成介质如VEGF、MMP2和MMP9以及炎性细胞因子IL6和TNFα表达受阻，从而引发病理生理学变化。结论：研究首次确定了溶菌酮通过靶向ATM/HIF-1α信号诱导抗血管生成的新作用。该研究突出了基于植物的草药溶菌酮的潜力，它可以通过靶向交织的信号交流来靶向癌症的多重特征。通过溶菌酮的这种方法，可在对抗癌症的复杂多样性中实现药物研发。版权所有 © 2023 Elsevier GmbH。保留所有权利。

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 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.Copyright © 2023 Elsevier GmbH. All rights reserved.