Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity

Lee, Su-Chan; Min, Hye‐Young; Choi, Hoon; Bae, Song Yi; Park, Kwan Hee; Hyun, Sangwon; Lee, Ho Jin; Moon, Jayoung; Park, Shin‐Hyung; Kim, Jun Yong; An, Hongchan; Park, So‐Jung; Seo, Ji Hae; Lee, Seungbeom; Kim, Young‐Myeong; Park, Hyun-Ju; Lee, Sang Kook; Lee, Jeeyeon; Kim, Kyu‐Won; Suh, Young-Ger

doi:10.1158/0008-5472.can-15-1492

Cited by 46 publications

(51 citation statements)

References 50 publications

(64 reference statements)

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“…We first observed that 1 treatment did not notably attenuate the expression of Hsp90 protein. In agreement with earlier studies474849, the expression of Hsp70 increased in a time-dependent manner, as an established marker for HSR after Hsp90 inhibition, while surprisingly the expression of HSF 1 protein was attenuated with 1 treatment in Molt 4 cells. As expected, the suppression of Hsp90 client proteins was observed, including p70 S6k , NFκB, Raf-1, p-GSK3β, MEK 1 and XIAP (pro-apoptotic protein), MDM 2 and Rb2 (oncoprotein), and CDK4 (cell cycle regulatory protein), HIF 1 and HSF1 (transcription factor) (Fig.…”

Section: Resultssupporting

confidence: 92%

“…It was reported that Hsp90 facilitates the proper folding of signaling proteins associated with cancer progression, tumor angiogenesis and therapy resistance by functioning as molecular chaperone, gaining attention as a target for therapeutic intervention474853. A growing body of evidence indicates that the accumulation of unfolding/misfolding proteins by the suppression of Hsp90 function assists several stresses, including ER stress overload, the ROS over-generation, and a functional disorder of the intracellular proteins, ultimately leading to ER stress-induced apoptosis, if unfolding is overwhelming54555657.…”

Section: Discussionmentioning

confidence: 99%

“…Cumulative evidence suggests that several C-terminal Hsp90 inhibitors, as an alternatively clinical target, possess antiproliferative and apoptotic activities without eliciting heat shock response (HSR)474849. Previous studies have indicated that activation of HSF 1 (Heat Shock Factor 1) is critical for the induction of HSR and may confer acquired resistance of Hsp90 inhibitors6465.…”

Section: Discussionmentioning

confidence: 99%

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Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Lai

Liu

et al. 2016

Sci Rep

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Two new scalarane sesterterpenoids, 12β-(3′β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(3′β-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70S6k, NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Lai

Liu

et al. 2016

Sci Rep

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“…Our current study demonstrates for the first time that deguelin, a rotenoid derived from Mundulea sericea (Willd) [15][16][17] with a chemical structure distinct from CQ, is a novel late-stage autophagy inhibitor. Previous reports have shown that deguelin inhibits the survival of various cancer cells through mechanisms including DNA damage induction, reduced expression of DNA repair genes, inhibition of vasculogenic function, and blockage of anti-apoptotic pathways [13,25,26].…”

Section: Discussionmentioning

confidence: 77%

“…Previous studies have shown that deguelin induces apoptosis in cancer cells by targeting the AMPK and PI3K/Akt pathway [16,17]. Furthermore, deguelin inhibits the growth and metastasis of pancreatic cancer cells both in vivo and in vitro [18].…”

Section: Introductionmentioning

confidence: 98%

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

Zhao

Zhang

et al. 2016

Preprint

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Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

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An Outbreak of Fungal Endophthalmitis After Cataract Surgery in South Korea

Kim

Choi

et al. 2023

JAMA Ophthalmol

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ImportanceFungal endophthalmitis caused by contaminated medical products is extremely rare; it follows an intractable clinical course with a poor visual prognosis.ObjectiveTo report the epidemiologic and clinical features and treatment outcomes of a nationwide fungal endophthalmitis outbreak after cataract surgery as a result of contaminated viscoelastic agents in South Korea.Design, Setting, and ParticipantsThis was a retrospective case series analysis of clinical data from multiple institutions in South Korea conducted from September 1, 2020, to October 31, 2021. Data were collected through nationwide surveys in May and October 2021 from the 100 members of the Korean Retinal Society. Patients were diagnosed with fungal endophthalmitis resulting from the use of the viscoelastic material sodium hyaluronate (Unial [Unimed Pharmaceutical Inc]). Data were analyzed from November 1, 2021, to May 30, 2022.Main Outcomes and MeasuresThe clinical features and causative species were identified, and treatment outcomes were analyzed for patients who underwent 6 months of follow-up.ResultsThe fungal endophthalmitis outbreak developed between September 1, 2020, and June 30, 2021, and peaked in November 2020. An official investigation by the Korea Disease Control and Prevention Agency confirmed contamination of viscoelastic material. All 281 eyes of 265 patients (mean [SD] age, 65.4 [10.8] years; 153 female individuals [57.7%]) were diagnosed with fungal endophthalmitis, based on clinical examinations and supportive culture results. The mean (SD) time period between cataract surgery and diagnosis was 24.7 (17.3) days. Patients exhibited characteristic clinical features of fungal endophthalmitis, including vitreous opacity (212 of 281 [75.4%]), infiltration into the intraocular lens (143 of 281 [50.9%]), and ciliary infiltration (55 of 281 [19.6%]). Cultures were performed in 260 eyes, and fungal presence was confirmed in 103 eyes (39.6%). Among them, Fusarium species were identified in 89 eyes (86.4%). Among the 228 eyes included in the treatment outcome analysis, the mean (SD) best-corrected visual acuity improved from 0.78 (0.74) logMAR (Snellen equivalent, 20/120 [7.3 lines]) to 0.36 (0.49) logMAR (Snellen equivalent, 20/45 [4.9 lines]) at 6 months. Furthermore, disease remission with no signs of fungal endophthalmitis (or cells in the anterior chamber milder than grade 1) was noted in 214 eyes (93.9%).Conclusions and RelevanceThis was a retrospectively reviewed case series of a fungal endophthalmitis outbreak resulting from contaminated viscoelastic material. Findings of this case series study support the potential benefit of prompt, aggressive surgical intervention that may reduce treatment burden and improve prognosis of fungal endophthalmitis caused by contaminated medical products.

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Deguelin Analogue SH-1242 Inhibits Hsp90 Activity and Exerts Potent Anticancer Efficacy with Limited Neurotoxicity

Abstract: The Hsp90 facilitates proper folding of signaling proteins associated with cancer progression, gaining attention as a target for therapeutic intervention.

Cited by 46 publications

References 50 publications

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Antileukemic Scalarane Sesterterpenoids and Meroditerpenoid from Carteriospongia (Phyllospongia) sp., Induce Apoptosis via Dual Inhibitory Effects on Topoisomerase II and Hsp90

Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

An Outbreak of Fungal Endophthalmitis After Cataract Surgery in South Korea

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