Cucurbitacin B: A review of its pharmacology, toxicity, and pharmacokinetics

Dai, Shu-Ho; Wang, Cheng; Zhao, Xingtao; Ma, Cheng; Fu, Ke; Liu, Yanfang; Peng, Cheng Yuan; Li, Yunxia

doi:10.1016/j.phrs.2022.106587

Cited by 43 publications

(30 citation statements)

References 152 publications

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“…Cucurbitacin B (CuB) is a highly oxidized tetracyclic triterpenoid found in a wide range of plants, particularly within the Cucurbitaceae family. Its anti-inflammatory, antioxidant, and anti-cancer properties have been demonstrated through a range of mechanisms, such as epigenetic modifications and/or alterations to cellular pathways following treatment [ 130 ]. For example, Shukla et al observed that CuB inhibited DNA methyltransferases and histone deacetylases in H1299 cells while reactivating two tumor suppressor genes ( CDKN1A and CDKN2A ), downregulating two oncogenes ( c-MYC and K-RAS ), and silencing the human telomerase reverse transcriptase gene ( hTERT ) [ 131 ].…”

Section: Detailed Results and Discussionmentioning

confidence: 99%

“…As a result of their activity, either the upregulation of HAT or the downregulation of HDAC can be observed, and the expression of miRNA and lncRNA genes, responsible for tumor development and metastasis, can be modulated [ 103 , 105 , 139 ]. They can also modify the histones of the promoter of tumor-related pathways’ genes and directly affect the expression of oncogenes and tumor suppressor genes [ 104 , 106 , 111 , 116 , 124 , 130 ].…”

Section: Detailed Results and Discussionmentioning

confidence: 99%

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A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

Sulewska

Pilz

Manegold

et al. 2023

Cells

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Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

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Section: Detailed Results and Discussionmentioning

confidence: 99%

Section: Detailed Results and Discussionmentioning

confidence: 99%

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

Sulewska

Pilz

Manegold

et al. 2023

Cells

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“…Cucurbitacin B (CuB, 1 ) is the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. , This compound could inhibit the proliferation of various tumors in vitro and in vivo, including liver cancer, breast cancer, myeloid leukemia, renal cell carcinoma, prostate cancer, non-small cell lung cancer (NSCLC), and so on. , Accumulating evidence has revealed that the antiproliferative activity of CuB is mainly achieved by inhibiting cell growth and proliferation, arresting the cell cycle, inducing cell apoptosis, destroying the cytoskeleton, inhibiting cell migration and invasion, as well as inducing cell autophagy. , Recently, Tu et al elucidated the antitumor molecular mechanism of CuB and identified IGF2BP1 as a novel target of CuB. They demonstrated that CuB is an irreversible covalent inhibitor of IGF2BP1 and forms a covalent bond with cysteine 253 of the IGF2BP1 KH 1–2 domain through α, β-unsaturated ketone to block the interaction between IGF2BP1 and m 6 A. Consequently, CuB destabilizes IGF2BP1-regulated target mRNA and induces tumor cell apoptosis, which in turn attracts immune cells to the tumor microenvironment. , However, strong toxic side effects and a narrow therapeutic window seriously affect its clinical application . Therefore, the development of highly effective and low toxicity CuB derivatives through structural modifications is a research direction that many pharmaceutical chemists are committed to pursuing.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Accumulating evidence has revealed that the antiproliferative activity of CuB is mainly achieved by inhibiting cell growth and proliferation, arresting the cell cycle, inducing cell apoptosis, destroying the cytoskeleton, inhibiting cell migration and invasion, as well as inducing cell autophagy. 5,6 Recently, Tu et al elucidated the antitumor molecular mechanism of CuB and identified IGF2BP1 as a novel target of CuB. They demonstrated that CuB is an irreversible covalent inhibitor of IGF2BP1 and forms a covalent bond with cysteine 253 of the IGF2BP1 KH 1−2 domain through α, β-unsaturated ketone to block the interaction between IGF2BP1 and m 6 A. Consequently, CuB destabilizes IGF2BP1-regulated target mRNA and induces tumor cell apoptosis, which in turn attracts immune cells to the tumor microenvironment.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

Shang,

Lu,

Lin

et al. 2023

J. Med. Chem.

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Cucurbitacin B (CuB) is a potent but toxic anticancer natural product. Herein, we designed and synthesized 2-OH-and 16-OH-modified CuB derivatives to improve their antitumor efficacy and reduce toxicity. Among them, derivative A11 had the most potent antiproliferative activity against A549 lung cancer cells (IC 50 = 0.009 μM) and was approximately 10-fold more potent than CuB, while the cytotoxicity of A11 toward normal L02 cells was about 10-fold less potent, indicating a much wider therapeutic window than CuB. Derivative A11 directly binds to the insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) protein with a K D value of 2.88 nM, which is about 23fold more potent than CuB, leading to the decreased expression of downstream apoptosis-and cell cycle-related proteins. More importantly, A11 exhibited much more potent anticancer efficacy in an A549 xenograft mouse model with a TGI rate of 80% and a superior in vivo safety profile than that of CuB.

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Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

Niu,

Liu,

Gao

et al. 2023

Anim Models and Exp Med

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BackgroundBitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances. Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo.MethodsTo investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues, multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene‐editing technique. A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes. Then, T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice. Quantitative real‐time polymerase chain reaction (qRT‐PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds. Perception to taste substance was also studied using two‐bottle preference tests.ResultsWe successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique. Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice. But qRT‐PCR results revealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice. With two‐bottle preference tests, these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105. In addition, these mutant mice showed a loss of taste perception to quinine dihydrochloride, denatonium benzoate, and cucurbitacin B (CuB). Gnat3‐mediated taste receptor and its signal pathway contribute to CuB perception.ConclusionsThese findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound–induced responses mediated by these TAS2Rs in many extraoral tissues.

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Cucurbitacin B: A review of its pharmacology, toxicity, and pharmacokinetics

Cited by 43 publications

References 152 publications

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

Genetic mutation of Tas2r104/Tas2r105/Tas2r114 cluster leads to a loss of taste perception to denatonium benzoate and cucurbitacin B

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