Identification of osalmid metabolic profile and active metabolites with anti-tumor activity in human hepatocellular carcinoma cells

Wu, Zhe; Zhan, Yaqiong; Wang, Li; Tong, Jijun; Zhang, Li; Lin, Mengjia; Jin, Xuehang; Jiang, Lushun; Lou, Yan; Qiu, Yunqing

doi:10.1016/j.biopha.2020.110556

Cited by 10 publications

(11 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our results showed that HDS displayed growth inhibition in all tested cell lines, regardless of p53 status. On one hand, the accumulated DNA damage caused by HDS can promote cell apoptosis by activating p53 [ 22 ]; on the other hand, the accumulated DNA damage can promote cell death in a p53-independent pathway. For example, although p53 plays a central role in DNA damage-induced cell death, p53-mutant cells may still die from DNA damage due to catastrophic mitotic death [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Besides, HDS is reported to efficiently inhibit the replication of hepatitis B virus with limited toxicity in vitro and in vivo [ 20 , 21 ]. Moreover, active metabolites of HDS are reported to induce hepatocellular carcinoma cell apoptosis by activating p53-related pathways [ 22 ]. Therefore, given the clinical advantages of HDS and its potential effect on inducing cell apoptosis, we wondered whether HDS could play a role in MM.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma

Xie

Wang

et al. 2022

J Biomed Sci

View full text Add to dashboard Cite

Background Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM. Methods We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy. Results HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM. Conclusions Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM. Trial registration: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma

Xie

Wang

et al. 2022

J Biomed Sci

View full text Add to dashboard Cite

show abstract

“…Metabolomics has been redefined as the technology for discovering active factors of biological and pathological processes ( 16 ). Metabolomics can be harnessed to identify the metabolites that act as regulators of biological processes ( 17 , 18 ), providing novel insights into the active role of metabolites in physiology and diseases. For example, phospholipids, sphingolipids, and methionine can act as regulators of insulin sensitivity and metabolism ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

et al. 2021

View full text Add to dashboard Cite

Polycystic ovary syndrome (PCOS) is a complex reproductive, endocrine, and metabolic disorder in reproductive-age women. In order to explore the active metabolites of brown adipose tissue (BAT) transplantation in improving the reproductive and metabolic phenotypes in a PCOS rat model, the metabolites in the recipient’s BAT were explored using the liquid chromatography–mass spectrometry technique. In total, 9 upregulated and 13 downregulated metabolites were identified. They were roughly categorized into 12 distinct classes, mainly including glycerophosphoinositols, glycerophosphocholines, and sphingolipids. Ingenuity pathway analysis predicted that these differentially metabolites mainly target the PI3K/AKT, MAPK, and Wnt signaling pathways, which are closely associated with PCOS. Furthermore, one of these differential metabolites, sphingosine belonging to sphingolipids, was randomly selected for further experiments on a human granulosa-like tumor cell line (KGN). It significantly accelerated the apoptosis of KGN cells induced by dihydrotestosterone. Based on these findings, we speculated that metabolome changes are an important process for BAT transplantation in improving PCOS. It might be a novel therapeutic target for PCOS treatment.

show abstract

“…Sorafenib induces ferroptosis of cancer cells in HCC and is the first systemic molecular-targeted therapy drug approved by the FDA for advanced HCC [ 27 ]. Interestingly, RRM2 has been demonstrated as a novel target of sorafenib [ 28 ], and the inhibition of RRM2 activity significantly inhibited HCC progression [ 29 ]. These results demonstrate that therapeutic agents against HCC that affect iron levels also effect RRM2, indicating the role of RRM2 in iron metabolism in HCC.…”

Section: Discussionmentioning

confidence: 99%

A novel four-gene of iron metabolism-related and methylated for prognosis prediction of hepatocellular carcinoma

Shen

Sun

et al. 2020

Bioengineered

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a liver disease with a complex underlying mechanism, and patients with HCC have low survival rates. Iron metabolism plays a crucial role in the pathogenesis of HCC; however, the prognostic value of iron metabolism-related and methylated genes for HCC needs to be further explored. In the present study, we identified differentially expressed genes (DEGs) that play a role in iron metabolism and DNA methylation in HCC from The Cancer Genome Atlas. Four of these DEGs, whose expression levels are correlated with HCC prognosis, namely, RRM2, FTCD, CYP2C9, and ATP6V1C1, were further used to construct a prognostic model for HCC, wherein the risk score was calculated using the gene expression of the four DEGs. This could be used to predict the overall survival of HCC patients for 1, 3, and 5 years. Results of a multivariate Cox regression analysis further indicated that the risk score was an independent variable correlated with the prognosis of HCC patients. The identified gene signature was further validated using an independent cohort of HCC patients from the International Cancer Genome Consortium. Weighted gene co-expression network analysis and gene set enrichment analysis were performed to identify potential regulatory mechanisms of the gene signature in HCC. Taken together, we identified key prognostic factors of iron metabolism-related and methylated genes for HCC, providing a potential treatment strategy for HCC.

show abstract

Identification of osalmid metabolic profile and active metabolites with anti-tumor activity in human hepatocellular carcinoma cells

Cited by 10 publications

References 41 publications

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma

Preclinical validation and phase I trial of 4-hydroxysalicylanilide, targeting ribonucleotide reductase mediated dNTP synthesis in multiple myeloma

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

A novel four-gene of iron metabolism-related and methylated for prognosis prediction of hepatocellular carcinoma

Contact Info

Product

Resources

About