Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Liu, Chuanxu; Yin, Qianqian; Zhou, Huchen; Wu, Yingli; Pu, Jian‐Xin; Li, Xia; Liu, Wei; Huang, Xin; Jiang, Tao; Wu, Mingxuan; He, Licai; Zhao, Yulan; Wang, Xiaolin; Xiao, Wei‐Lie; Chen, Hongzhuan; Zhao, Qian; Zhou, Aiwu; Wang, Li‐Shun; Sun, Han‐Dong; Chen, Guoqiang

doi:10.1038/nchembio.935

Cited by 185 publications

(223 citation statements)

References 45 publications

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“…Identifying the direct targets of natural products is critical for understanding their inherent molecular mechanisms and acceler-ating the progress of drug discovery, but it is a rather challenging process (25). In this study, we revealed that vibsanin B preferentially targets HSP90b and has a very weak binding with HSP90a through activity-based protein profiling method (40), indicating that inhibition of HSP90b, but not HSP90a, would be mainly responsible for the inhibitory effect of vibsanin B on leukocyte migration.…”

Section: Discussionmentioning

confidence: 78%

“…Natural products, which possess extraordinary biological specificity and potency compared with artificially designed molecules because of evolutionary selection (35), have promoted the development of most new drugs (36). They not only are fantastic chemical probes to fish novel insights into biological processes, but also serve as drug leads for the development of therapeutic agents against a variety of diseases (25).…”

Section: Discussionmentioning

confidence: 99%

“…2D), followed by mass spectrometry analysis (25). Biotin-ViB partially retained its inhibitory effect on leukocyte migration (Supplemental Fig.…”

Section: Vibsanin B Preferentially Targets Hsp90bmentioning

confidence: 99%

“…Vibsanin B contains a,b-unsaturated moieties, namely Michael acceptors (25), which potentially react with positionally suited nucleophiles, such as hydrosulfuryl groups and amino groups. This Fig.…”

Section: Identification Of Vibsanin B That Inhibits Leukocyte Migratimentioning

confidence: 99%

“…Pull-down assay and mass spectrum analysis As described in previous work (25), THP-1 cell lysates were incubated with biotin or biotin-tagged vibsanin B (Biotin-ViB) in the absence or presence of vibsanin B at 4˚C, followed by incubation with streptavidin-agarose beads (Sigma-Aldrich, catalog no. S1638).…”

Section: Transwell Assaymentioning

confidence: 99%

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Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Deng

Shao

et al. 2015

The Journal of Immunology

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Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz–enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B’s effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

“…2D), followed by mass spectrometry analysis (25). Biotin-ViB partially retained its inhibitory effect on leukocyte migration (Supplemental Fig.…”

Section: Vibsanin B Preferentially Targets Hsp90bmentioning

confidence: 99%

Section: Identification Of Vibsanin B That Inhibits Leukocyte Migratimentioning

confidence: 99%

Section: Transwell Assaymentioning

confidence: 99%

See 3 more Smart Citations

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Deng

Shao

et al. 2015

The Journal of Immunology

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Targeting the thioredoxin system as a novel strategy against B‐cell acute lymphoblastic leukemia

et al. 2019

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B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR‐ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP‐ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP‐ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP‐ALL cell lines and pediatric and adult BCP‐ALL primary cells, including primary cells cocultured with bone marrow‐derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL ‐rearranged patient‐derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP‐ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti‐BCP‐ALL drugs should be continued.

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Natural Product Synthesis for Drug Discovery and Chemical Biology

Yao

Wei

2018

Efficiency in Natural Product Total Synthesis

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Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Cited by 185 publications

References 45 publications

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Vibsanin B Preferentially Targets HSP90β, Inhibits Interstitial Leukocyte Migration, and Ameliorates Experimental Autoimmune Encephalomyelitis

Targeting the thioredoxin system as a novel strategy against B‐cell acute lymphoblastic leukemia

Natural Product Synthesis for Drug Discovery and Chemical Biology

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