Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance

Zhang, Yun-Kai; Wang, Yijun; Vispute, Saurabh; Jain, Sandeep; Chen, Yangmin; Li, Jessalyn; Youssef, Diaa T. A.; Sayed, Khalid A. El; Chen, Zhe‐Sheng

doi:10.3390/md13042267

Cited by 19 publications

(17 citation statements)

References 31 publications

(34 reference statements)

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“…In silico molecular docking study, by the inspection of the virtual binding modes of compounds 5 and 6 into human homology model of P-gp, revealed that both compounds were overlapped but with different molecular orientation of ester substituents. Their strong affinity and specificity to P-gp expressing efflux protein indicated that compounds 5 and 6 may represent a potential reversal agents for treatment of MDR cancers [39]. The synthesis of the ester analogs 8 and 9 is presented in Scheme 1, to highlight the strategy involved (using a ligand-based design approach).…”

Section: Sipholane Triterpenoids and Derivativesmentioning

confidence: 99%

“…This class of triterpenes consists of sipholenol A (1), sipholenone E (2), sipholenol L (3), and siphonellinol D (4), isolated from the Red Sea sponge Callyspongia siphonella [44,45], and semisynthetic derivatives of sipholenol A such as sipholenol A-4-O-acetate (5), sipholenol A-4-O-isonicotinate (6) [39], sipholenol A-4-O-3',4'-dichlorobenzoate (7) [46], sipholenol A 4-O-4'-chlorobenzoate (8), and 19,20-anhydrosipholenol A 4-O-4'-chlorobenzoate (9) [47] that were synthesized using a ligand-based design approach. Natural and semisynthetic siphonane triterpenoids were shown to reverse MDR activities (1-6), and display antimigratory and antiproliferative activities in breast cancer cell lines (7)(8)(9).…”

Section: Sipholane Triterpenoids and Derivativesmentioning

confidence: 99%

“…There are already several reviews which highlighted the importance of marine natural products in cancer and, in particular, as P-gp modulators [29,35,[39][40][41][42][43]. However, this review aims to describe not only the effects of the most valuable scaffolds from marine natural products and analogs in overcoming MDR but also their synthetic pathways.…”

Section: Introductionmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

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Section: Sipholane Triterpenoids and Derivativesmentioning

confidence: 99%

Section: Sipholane Triterpenoids and Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Marine Natural Products as Models to Circumvent Multidrug Resistance

et al. 2016

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“…Over the past three decades, a number of efflux function modulators have been developed and investigated for their inhibitory action against ABCB1 and ABCG2-mediated MDR [7, 14-16]. Voruciclib, a CDK4/6 inhibitor, has shown promising anti-cancer effects in combination with the BRAF inhibitor, vemurafenib in advanced BRAF-mutant melanoma [17].…”

Section: Introductionmentioning

confidence: 99%

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Gupta

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: The overexpression of ATP-Binding Cassette (ABC) transporters has known to be one of the major obstacles impeding the success of chemotherapy in drug resistant cancers. In this study, we evaluated voruciclib, a CDK 4/6 inhibitor, for its chemo-sensitizing activity in ABCB1- and ABCG2- overexpressing cells. Methods: Cytotoxicity and reversal effect of voruciclib was determined by MTT assay. The intracellular accumulation and efflux of ABCB1 and ABCG2 substrates were measured by scintillation counter. The effects on expression and intracellular localization of ABCB1 and ABCG2 proteins were determined by Western blotting and immunofluorescence, respectively. Vanadate-sensitive ATPase assay was done to determine the effect of voruciclib on the ATPase activity of ABCB1 and ABCG2. Flow cytometric analysis was done to determine the effect of voruciclib on apoptosis of ABCB1 and ABCG2-overexpressing cells and docking analysis was done to determine the interaction of voruciclib with ABCB1 and ACBG2 protein. Results: Voruciclib significantly potentiated the effect of paclitaxel and doxorubicin in ABCB1-overexpressing cells, as well as mitoxantrone and SN-38 in ABCG2-overexpressing cells. Voruciclib moderately sensitized ABCC10- overexpressing cells to paclitaxel, whereas it did not alter the cytotoxicity of substrates of ABCC1. Furthermore, voruciclib increased the intracellular accumulation and decreased the efflux of substrate anti-cancer drugs from ABCB1- or ABCG2-overexpressing cells. However, voruciclib did not alter the expression or the sub-cellular localization of ABCB1 or ABCG2. Voruciclib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Lastly, voruciclib exhibited a drug-induced apoptotic effect in ABCB1- or ABCG2- overexpressing cells. Conclusion: Voruciclib is currently a phase I clinical trial drug. Our findings strongly support its potential use in combination with conventional anti-cancer drugs for cancer chemotherapy.

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“…[45] Three sipholanetriterpenes enhanced the cytotoxicity of several P-gp substrate anticancer drugs. [67] We have also reported a cytotoxic activity of sipholenone A, sipholenol A, and sipholenol L against A549 (Human Lung Carcinoma), MCF-7(Human Breast Adenocarcinoma) and PC-3 (Human Prostate Cancer). [8] Further, we have shown an observable activity against Caco-2, and HT-29 and HepG2 cells.…”

Section: Introductionmentioning

confidence: 98%

Cytotoxic metabolites from Callyspongia siphonella display antiproliferative activity by inducing apoptosis in HCT-116 cells

Sobahi¹,

Ayyad²,

Abdel‐Lateff³

et al. 2017

Phcog Mag

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Objectives:To evaluate the antiproliferative effect of the isolated metabolites from Callyspongia siphonella.Methods:Different chromatographic methods have been done on the organic extract of the marine sponge aiming at isolating the bioactive metabolites. The cytotoxicity of the isolated compounds has been evaluated against the human colorectal cancer cell line; HCT-116, employing SRB assay. The flow cytometry assay was applied to measure the cell cycle analysis.Results:Six metabolites (1–6) were obtained. The compounds 4–6 exhibited IC50 values (μM ± SD) of 95.80± 1.34, 14.8 ± 2.33, and 19.8 ± 3.78, respectively. Cell cycle distribution analysis revealed that sipholenol A (5) and sipholenol L (6) induced G2/M and S phase arrest with concomitant increase in the pre-G cell population. Furthermore, 5 and 6 increased the nuclear expression of the pro-apoptotic protein-cleaved caspase-3 that effectively drives cellular apoptosis via caspase-3-dependent pathway.Conclusions:The antiproliferative activity of 5 and 6 can be recognized, at least partly, due to their ability to induce cellular apoptosis.SUMMARYSeveral metabolites were isolated from the marine sponge Callyspongia siphonella. Sipholenol A and sipholenol L exhibited effective cytotoxicity against HCT-116 cells. The observed cytotoxicity involves induction of cellular apoptosis.Abbreviation used: A549 (human lung carcinoma), Caco-2 (Human ColonCarcinoma), CHCl3 (Chloroform), HCT 116 (Human Colon Carcinoma), HepG2 (Liver Hepatocellular Carcinoma), HT-29 (Human Colorectal Adenocarcinoma), MCF-7 (Michigan Cancer Foundation-7; Human Breast Adenocarcinoma), MeOH (Methanol), NMR Nuclear Magnetic Resonance), PBS (Phosphate Buffered Saline), PC-3 (Human Prostate Cancer), PTLC (Preparative Thin Layer Chromatography), RPMI-1640 (Roswell Park Memorial Institute medium), TLC (ThinLayer Chromatography).

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Esters of the Marine-Derived Triterpene Sipholenol A Reverse P-GP-Mediated Drug Resistance

Cited by 19 publications

References 31 publications

Marine Natural Products as Models to Circumvent Multidrug Resistance

Marine Natural Products as Models to Circumvent Multidrug Resistance

Voruciclib, a Potent CDK4/6 Inhibitor, Antagonizes ABCB1 and ABCG2-Mediated Multi-Drug Resistance in Cancer Cells

Cytotoxic metabolites from Callyspongia siphonella display antiproliferative activity by inducing apoptosis in HCT-116 cells

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