Panzem (2-methoxyestradiol) / CASI - LARVOL DELTA

HIF-1α-ASS1 axis drives reprogramming of arginine metabolism controls hepatic stellate cell activation in hepatic fibrosis. (PubMed, Phytomedicine) - "Genetic and pharmacological (ABRL8301, a 2-methoxyestradiol derivative) inhibition of hypoxia-inducible factor 1 alpha (HIF-1α) were assessed for effects on argininosuccinate synthetase 1 (ASS1) expression and antifibrotic efficacy in vitro and in vivo...Combination sorafenib and ABRL8301 therapy decreased MCHS compactness, increased apoptosis, and achieved superior tumor control in HCC xenografts...ABRL8301 acts as a pharmacologic inducer of ASS1 and arginine biosynthesis, inhibiting EMT and fibrotic progression while enhancing anticancer therapy. These findings support ABRL8301 as a promising antifibrotic and tumor-sensitizing agent in hepatic fibrosis."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Oncology • ASS1 • HIF1A • TGFB1

The regulatory effect of PI3K/Akt/HIF-1α glycolytic signaling pathway on the metabolites in urine of mice with bleomycin-induced pulmonary fibrosis model (PubMed, Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi) - " From May to October 2023, 36 C57BL/6 mice were randomly divided into six groups (n=6 each): control (BD) group, bleomycin model (BM) group, early PI3K inhibitor (LY294002) intervention (BZLY) group, late PI3K inhibitor intervention (BWLY) group, early HIF-1α inhibitor[2-methoxyestradiol(2-ME2) ] intervention (BZ2M) group, and late HIF-1α inhibitor intervention (BW2M) group. Pathway enrichment analysis revealed 6 significantly altered metabolic pathways: purine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, riboflavin metabolism, sphingolipid metabolism, and tyrosine metabolism (P<0.05) . The PI3K/Akt/HIF-1α glycolytic signaling pathway may regulate the development and progression of idiopathic pulmonary fibrosis through purine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, riboflavin metabolism, sphingolipid metabolism, and tyrosine metabolism pathways."

Journal • Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • HIF1A

ABRL8301, a Novel 2-Methoxyestradiol Derivative, Mitigates Progressive Pulmonary Fibrosis by Downregulating 11β-Hydroxysteroid Dehydrogenase 1. (PubMed, Eur J Pharmacol) - "Furthermore, ABRL8301 significantly attenuated PPF in both bleomycin- and radiation-induced mouse models, showing more pronounced histological and radiological improvement in lung consolidation and collagen deposition compared with nintedanib at the tested doses. ABRL8301 also mitigated radiation-induced skin vascular injury and collagen accumulation. Collectively, these findings identify ABRL8301 as a promising therapeutic candidate for PPF via the 11β-HSD1/HO-1/HIF-1α axis."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • HIF1A • HMOX1 • IL6

HIF-1α inhibits the TLR4/NF-κB signaling pathway and modulates intestinal flora in diarrhea-predominant irritable bowel syndrome. (PubMed, PLoS One) - "Under systemic hypobaric hypoxic stress, HIF-1α suppresses the TLR4/NF-κB signaling pathway and alleviates intestinal inflammatory responses. Concurrent intestinal hypoxia and inflammatory injury jointly interfere with normal commensal colonization, accompanied by altered gut microbial composition in IBS-D model rats. Changes in HIF-1α levels are biologically correlated with shifts in intestinal microbiota, though direct causal regulation of gut flora by HIF-1α remains to be verified in further experiments."

Journal • Gastrointestinal Disorder • Inflammation • Inflammatory Arthritis • Inflammatory Bowel Disease • HIF1A • TLR4

2-methoxyestradiol is effective in 2D and 3D models of NCI-H2170 lung squamous cell carcinoma cells. (PubMed, PLoS One) - "These results suggest that the HIF-1α inhibitor 2-methoxyestradiol, and three anti-infection agents (cetylpyridinium chloride, chlorhexidine-2HCl, zinc pyrithione) may be effective for metastatic LUSCs."

Journal • Infectious Disease • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • CREB3L1 • HIF1A

Bupleuri radix total saikosaponins alleviate liver fibrosis by inhibiting hepatic stellate cell activation via SIRT3-SMAD3/HIF-1α -mediated glycolysis. (PubMed, Phytomedicine) - "BRTS regulates the SMAD3/HIF-1α signalling axis through SIRT3 to mediate glycolysis in HSCs, which suppresses HSC activation and improves liver fibrosis."

Journal • Fibrosis • Hepatology • Immunology • Liver Cancer • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor • HIF1A • LDHA • PKM • SIRT3 • SLC2A1 • SMAD3 • TGFB1

2-Methoxyestradiol Suppresses Stemness and Epithelial-Mesenchymal Transition in Drug-Resistant Esophageal Squamous Cell Carcinoma by Targeting the Snail Signaling Pathway in Cancer Stem Cells. (PubMed, Stem Cell Rev Rep) - "Cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) are critical contributors to tumor drug resistance, which represents a major obstacle to successful cancer therapy. Collectively, our results reveal that 2ME2 effectively attenuates CSC stemness and inhibits EMT to overcome paclitaxel resistance in esophageal cancer. Accordingly, further development of more potent 2ME2 analogs and optimized delivery systems in future preclinical studies is warranted, which may provide therapy strategy for resistant ESCC treatment.Clinical Trial Registration: Not applicable."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

An antibody-conjugated polymer nanoparticle that targets inflammatory site for abdominal aortic aneurysm antioxidant stress therapy. (PubMed, Biomater Adv) - "Therefore, this study developed an antibody-conjugated sustained-release nanoparticle, which loaded 2-MEthoxyestradiol (2ME) and target AAA inflammatory sites by significantly reducing mitochondrial oxidative stress damage in vascular endothelial cells through surface conjugation with tocilizumab (TCZ). More importantly, PLGA-PEG nanocarrier-mediated drug delivery did not show significant organ toxicity such as liver and kidney in mice, demonstrating superior biocompatibility. This study reports an antibody-conjugated sustained-release nanodrug for targeted therapy of AAA, which provides a new treatment method for inflammatory vascular aneurysms."

Journal • Cardiovascular • Inflammation • IL6 • TFAM

BLCL-2ME-02: Multiple-Ascending Doses of 2-Methoxyestradiol in Healthy Non-Pregnant Female Participants. (clinicaltrialsregister.eu) - P1 | N=60 | Completed | Sponsor: Laboratorios Leon Farma S.A. | Recruiting ➔ Completed

Trial completion

Retraction: 2-Methoxyestradiol alleviates neuroinflammation and brain edema in early brain injury after subarachnoid hemorrhage in rats. (PubMed, Front Cell Neurosci) - "[This retracts the article DOI: 10.3389/fncel.2022.869546.]."

Journal • Preclinical • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology

The effect of the PI3K/Akt/HIF-1α signaling pathway in the changes of urinary metabolite in silicosis mice model (PubMed, Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi) - " From March to June 2023, 36 SPF-grade C57BL/6 mice were randomly divided into the control group, the silica (SiO(2)) model group, the PI3K inhibitor LY294002 early/late intervention group, and the HIF-1α inhibitor 2-methoxyestradiol (2-ME2) early/late intervention group, totaling 6 groups, with 6 mice in each group. Targeted interventions can mitigate pulmonary fibrosis damage by restoring core metabolite levels. The PI3K/Akt/HIF-1α signaling pathway may serve as a key mechanism regulating these metabolic abnormalities, providing an experimental foundation for early intervention and metabolic biomarker screening in pneumoconiosis."

Journal • Preclinical • Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • HIF1A

Gut microbiota dysbiosis induced by tibial dyschondroplasia in turn accelerates disease pathogenesis through the gut-bone axis in broilers. (PubMed, Poult Sci) - "Among them, chenodeoxycholic acid showed a strong positive correlation with Lactobacillus abundance and tibial mineral content, while 2-methoxyestradiol (an estrogen metabolite) exhibited inverse associations. Collectively, these findings provide evidence that gut microbiota dysbiosis causally contributes to TD and define the Lactobacillus-chenodeoxycholic acid axis and estrogen metabolism as promising targets for preventive and management strategies against TD in broilers."

Journal • Transplantation

A "one-two punch" strategy to reverse immunosuppressive metabolism and activate T-cell immunity for enhanced cancer checkpoint immunotherapy. (PubMed, J Nanobiotechnology) - "This is achieved by a nanoplatform, ipilimumab&2-methoxyestradiol @PLGA (IM@PLGA), which co-delivers the CTLA-4 antibody ipilimumab and 2-methoxyestradiol (2-ME). Furthermore, the treatment exhibits a potent abscopal effect in a metastatic tumor model. This work establishes a synergistic combination strategy that disrupts tumor metabolic defenses while boosting antitumor immunity, offering a promising approach to overcome resistance to cancer immune checkpoint blockade."

Journal • Oncology • HIF1A

An enzyme-responsive electrospun polyester membrane for sustained delivery of polymerized 2-methoxyestradiol to treat peritendinous adhesion. (PubMed, J Adv Res) - "The poly2ME2-loaded electrospun PCL membranes demonstrate enzyme-responsive controlled release and prevent peritendinous adhesion via inhibition of the HIF-1α/Sonic Hedgehog signaling pathway, providing a promising therapeutic biomaterial for the clinical prevention of tendon adhesion."

Journal • GLI1 • HIF1A • PTCH1

Synthesis of 2-aryl/alkylaminomethyl 17-sulfamate/17-methyl estratrienes and their in vitro cytotoxicity in human cancer cell cultures. (PubMed, Steroids) - "2-Methoxyestradiol (2-ME), a natural metabolite of 17β-estradiol, exhibits potent anticancer activity by inhibiting tubulin polymerization and modulating steroid sulfatase (STS)...Compared to literature on 2-ME sulfamates, our results show a distinct regioselectivity profile, with the 2‑aminomethyl scaffold favouring C‑17 sulfamoyation for maximum activity. This study offers the potential to develop estratriene-based anticancer agents with improved pharmacokinetic profiles."

Journal • Preclinical • Breast Cancer • Oncology

HIF1α mediates resistance to radiation and to KRAS inhibitors in pancreatic adenocarcinoma. (PubMed, PLoS One) - "To explore this, we conducted a drug repurposing screen and identified three HIF1α inhibitors (bakuchiol, BAY-87-2243, 2-methoxyestradiol) whose sensitivities were correlated with sensitivity to Deltarasin, a KRAS inhibitor. Our findings suggest that HIF1α inhibitors could be used to sensitize PDAC to radiotherapy and KRAS inhibitors."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • HIF1A • KRAS

BLCL-2ME-02: Multiple-Ascending Doses of 2-Methoxyestradiol in Healthy Non-Pregnant Female Participants. (clinicaltrialsregister.eu) - P1 | N=72 | Recruiting | Sponsor: Laboratorios Leon Farma S.A.

New P1 trial

Abatement of acrylonitrile-induced gastric injury by 2-Methoxyestradiol through inhibition of TLR4/MYD88/phospho-p38 MAPK axis. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Conclusively, 2ME ameliorates ACN-induced gastric injury. This protective effect may be associated with the antioxidant, anti-inflammatory, and anti-apoptotic properties of 2ME, in addition to a potential modulation of the TLR4/MYD88/phospho-p38 MAPK signaling pathway."

IO biomarker • Journal • B Cell Lymphoma • Lymphoma • Oncology • BCL2 • CAT • IL6 • MYD88 • TLR4 • TNFA

Taohong Siwu Decoction Regulates MSC-Mediated H-Type Angiogenesis to Accelerate Bone Fracture Healing Through VHL/HIF-1α Ubiquitination. (PubMed, Mediators Inflamm) - "Additionally, MSCs were treated with paeoniflorin and 2-methoxyestradiol (2-ME2) to explore the effects of paeoniflorin...In summary, TSD affects H-type angiogenesis and MSCs homing during the healing process of fractured mice through the HIF-1α axis. TSD regulated MSC-mediated H-type angiogenesis to accelerate fracture healing through VHL/HIF-1α ubiquitination."

Journal • Musculoskeletal Diseases • Orthopedics • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • CD31 • EMCN • HIF1A • PECAM1 • THY1 • VHL

Hypoxia-Inducible-Factor mediates tissue-specific mitochondrial responses to acute hypoxia in mice but not in rats. (PubMed, Respir Physiol Neurobiol) - "To determine whether these effects were HIF-dependent, a group of animals were also treated with deferoxamine (a HIF stabilizer) under normoxia or with 2-methoxyestradiol (a HIF inhibitor) under hypoxia. In contrast, OCR remained unchanged in the cerebral cortex of mice and in both tissues of rats, indicating species- and tissue-specific regulation. These findings reveal that HIF activation under acute hypoxia selectively modulates liver mitochondrial function in mice but not in rats, supporting the view that interspecific differences in HIF-mediated metabolic regulation contribute to the superior hypoxic tolerance of mice."

Journal • Preclinical • HIF1A

Electroacupuncture improves hypoxic stress and energy metabolism to alleviate vascular cognitive impairment through activation of the HIF-1α/p53/NGB signaling pathway in rats. (PubMed, Iran J Basic Med Sci) - "Thirty minutes prior to EA, the hypoxia-inducible factor-1α (HIF-1α) inhibitor 2-methoxyestradiol (2ME2) was injected intraperitoneally...Notably, the beneficial effects of EA on cerebral energy metabolism were abolished by 2ME2 in VCI model rats. EA alleviated BCCAO-induced neurological impairment and cognitive dysfunction in rats, possibly by reducing hypoxic stress and enhancing energy metabolism in the cortex and hippocampus, potentially through modulation of the HIF-1α/p53/NGB signaling pathway."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • HIF1A • HMOX1

BMAL1 Downregulation Exacerbates Age-related Nonalcoholic Steatohepatitis by Promoting NLRP3 Inflammasome Activation via HIF-1ɑ-mediated Glycolysis. (PubMed, Free Radic Biol Med) - "This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis."

Journal • Acute Myelogenous Leukemia • Fibrosis • Hepatitis B • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • ARNTL • BMAL1 • HIF1A • NLRP3

Hypoxic conditions confer chemoresistance to crizotinib but not to imatinib in chronic myeloid leukemia cells. (PubMed, Hematol Transfus Cell Ther) - "In summary, this study shows the critical role of selective targeting of components of the HIF1α signaling pathway for the complete eradication of chronic myeloid leukemia cells."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • HIF1A

Combined HIF-1α blockade and CHIR99021 treatment reverses pulmonary fibrosis via modulation endothelial-to-mesenchymal transition. (PubMed, iScience) - "We demonstrate that the dual inhibition of HIF-1α and GSK-3β with 2-methoxyestradiol (2-ME) and CHIR99021 reverses fibrotic alterations in endothelial cells and pulmonary fibroblasts, accompanied by reduced DNA damage foci...In fibroblasts from patients with idiopathic pulmonary fibrosis, the therapy reduced profibrotic gene expression, proliferation, and matrix remodeling. These findings highlight dual HIF-1α/GSK-3β targeting to reverse fibrosis through coordinated EndMT suppression, DNA repair, and chromatin remodeling."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • HIF1A

Mucinous cystic neoplasms of the pancreas demonstrate in situ production of estrogen. (PubMed, Front Cell Dev Biol) - "We identified that relative to histologically normal pancreas, and intraductal papillary mucinous neoplasm (IPMN), the stroma in MCN expresses significantly greater levels of estrone (E1), estradiol (E2), estriol (E3), 2-hydroxyestradiol (2-OHE2), 2-methoxyestrone (2-MeOE1), 2-methoxyestradiol (2-MeOE2) and 16α-hydroxyestrone (16α-OHE1), at levels similar to those seen in the stroma in the normal ovary. These findings establish the functional capability of the ova rian-type stroma in MCN tumors for endogenous hormone production and show that the levels of estrogen in the stroma of MCN tumors approach those of the ovary. These findings serve as a basis for future studies examining the systemic effects of estrogen and the effects of estrogen on tumor progression, both in MCN tumors and tumor metastatic to the ovary."

Journal • CNS Tumor • Oncology • Pancreatic Cancer • Solid Tumor