2-Oxonanonoidal Antibiotic Actinolactomycin Inhibits Cancer Progression by Suppressing HIF-1α

Abstract

HIF-1 serves as an important regulator in cell response to hypoxia. Due to its key role in promoting tumor survival and progression under hypoxia, HIF-1 has become a promising target of cancer therapy. Thus far, several HIF-1 inhibitors have been identified, most of which are from synthesized chemical compounds. Here, we report that ALM (ActinoLactoMycin), a compound extracted from metabolites of Streptomyces flavoretus, exhibits inhibitory effect on HIF-1α. Mechanistically, we found that ALM inhibited the translation of HIF-1α protein by suppressing mTOR signaling activity. Treatment with ALM induced cell apoptosis and growth inhibition of cancer cells both in vitro and in vivo in a HIF-1 dependent manner. More interestingly, low dose of ALM treatment enhanced the anti-tumor effect of Everolimus, an inhibitor of mTOR, suggesting its potential use in combination therapy of tumors, especially solid tumor patients. Thus, we identified a novel HIF-1α inhibitor from the metabolites of Streptomyces flavoretus, which shows promising anti-cancer potential.

Anti-inflammatory and immunosuppressant activity of Coprinus comatus ethanol extract in carrageenan-induced rats (Rattus norvegicus)

“…In addition to phenolic compounds that can act as antioxidants, others also have anti-inflammatory and immunomodulatory roles. Previous studies on clinical applications reported that the compound 2oxonanone (CAS) plays a role in inhibiting cancer development by suppressing HIF-1α (Cheng et al, 2019). The qualitative identification of C. comatus contains alkaloids, saponins, flavonoids, polyphenol, and phenolic.…”

LncRNA OIP5-AS1 Regulates the Warburg Effect Through miR-124-5p/IDH2/HIF-1α Pathway in Cervical Cancer

“…Although this study is not related to tumors, not even in human cells, this study at least suggests that OIP5-AS1 may regulate HIF1-expression. HIF-1α is ubiquitous in human and mammalian cells and is also expressed under normal oxygen (21% O2) (Cheng et al, 2019;Miska et al, 2019), but the synthetic HIF-1 protein is quickly degraded by the intracellular oxygen-dependent ubiquitin protease degradation pathway (Oh et al, 2016;He et al, 2017), and can be stably expressed under hypoxia (Wang and Semenza, 1995;Salceda and Caro, 1997). It was well know that hypoxia contributes to the Warburg effect through the regulation of expression of HIF-1α (Yang et al, 2014;Liu et al, 2016), whether OIP5-AS1 regulates the Warburg effect in cervical cancer cells through HIF-1α remains uncharacterized.…”

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

“…Moreover, using low concentrations of ALM resulted in an enhanced effect of Everolimus, an inhibitor of mTOR already used in anti-cancer therapy. 68 The combination of ALM and Everolimus enables a lower drug dose and more efficient therapy for solid tumor patients. 68 Zebularine, the analog of cytidine belonging to a group of DNA methyltransferases, also shows a downregulation effect on HIF-1α expression.…”

“… 68 The combination of ALM and Everolimus enables a lower drug dose and more efficient therapy for solid tumor patients. 68 Zebularine, the analog of cytidine belonging to a group of DNA methyltransferases, also shows a downregulation effect on HIF-1α expression. Using this compound in the study of the human colorectal cancer line (HCT116) and tumor xenografts resulted in the degradation of HIF-1α protein and the reduction of angiogenesis.…”