Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma

Sadhu, M Naveen; Dhanalakshmi, Sivanandhan; Gajendran, Chandru; Tantry, Subramanyam J.; Dewang, Purushottam; Murugan, K; Chickamunivenkatappa, Srinatha; Zainuddin, Mohd; Nair, S. Asha; Vaithilingam, Krishnakumar; Rajagopal, Sridharan

doi:10.1016/j.bmcl.2020.127763

Cited by 24 publications

(21 citation statements)

References 31 publications

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“…ROS level was detected by flow cytometry in gastric cancer cells. The cells pretreated with NAC for 1 h blocked the production of ROS and prevented the upregulation of DR5, as well as mitochondria JNK-CHOP pathway (18). ROS triggered apoptosis by activating death receptors and the mitochondria pathway (19,20).…”

Section: Discussionmentioning

confidence: 90%

“…The death rate of patients suffering from gastric cancer is increasing. The emergence of side effects and multi-drug resistance to chemotherapeutic drugs usually lead to the failure of chemotherapies (18). In this study, a new Indole compound LCT-3d was discovered, which had selective cytotoxicity against gastric cancer cells with no apparent cytotoxicity against nonmalignant gastric epithelial cells.…”

Section: Discussionmentioning

confidence: 98%

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LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

Wang

Wu²,

Yu³

et al. 2021

Front. Oncol.

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Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis via mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can’t reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis via DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 98%

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

Wang

Wu²,

Yu³

et al. 2021

Front. Oncol.

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“…The structure of one of the leads JBI-097 is depicted in the Fig 1A . We recently published the results of the SAR analysis, PK profile and synthetic methodology of JBI-097 and other various compounds [ 29 ]. Here in we describe the biological characterization of the lead molecule JBI-097.…”

Section: Resultsmentioning

confidence: 99%

Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer

Gajendran

Tantry

et al. 2023

PLoS ONE

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Dually targeting the epigenetic proteins lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) that play a key role in cancer cells by modulating gene repressor complexes including CoREST will have a profound effect in inhibiting tumour growth. Here, we evaluated JBI-097 a dual LSD1/HDAC6 inhibitor, for its in vitro and in vivo activities in various tumor models. In vitro, JBI-097 showed a strong potency in inhibiting LSD1 and HDAC6 enzymatic activities with the isoform selectivity over other HDACs. Cell-based experiments demonstrated a superior anti-proliferative profile against haematological and solid tumor cell lines. JBI-097 also showed strong modulation of HDAC6 and LSD1 specific biomarkers, alpha-tubulin, CD86, CD11b, and GFi1b. In vivo, JBI-097 showed a stronger effect in erythroleukemia, multiple myeloma xenograft models, and in CT-26 syngeneic model. JBI-097 also showed efficacy as monotherapy and additive or synergistic efficacy in combination with the standard of care or with immune checkpoint inhibitors. These and other findings suggest that JBI-097 could be a promising molecule for targeting the LSD1 and HDAC6. Further studies are warranted to elucidate the mechanism of action.

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“…Our results suggest a similar outcome could be achieved through the combination of single mechanism LSD1 and HDAC6 inhibitors. While our work was in progress, dual inhibition of LSD1 and HDAC6 was shown to be beneficial in cell-based and animal models of multiple myeloma as well [ 33 ].…”

Section: Resultsmentioning

confidence: 99%

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

Bulut

Lee

Cevatemre

et al. 2022

Cancers

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Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.

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Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma

Cited by 24 publications

References 31 publications

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

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