A novel mechanism of irinotecan targeting MDM2 and Bcl-xL

Lee, Boah; Min, Jeong A.; Nashed, Abdullateef; Lee, Sang-Ok; Yoo, Jae Cheal; Chi, Seung‐Wook; Yi, Gwan‐Su

doi:10.1016/j.bbrc.2019.04.009

Cited by 17 publications

(7 citation statements)

References 21 publications

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“…S3 B and C ). Since etoposide and irinotecan are topoisomerase inhibitors (16, 17) and oxaliplatin induces DNA adducts (18), it is conceivable that these 5-FU-resistant cells may have additional mutations affecting DNA repair pathways differentially, independent of BOK status. Consistent with this notion, BOK −/− cells were sensitive to oxaliplatin and had a robust p53 response, determined by a p53-GFP reporter (ref.…”

Section: Resultsmentioning

confidence: 99%

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

Srivastava

Cao

Nedeva

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of Bok results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.

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Section: Resultsmentioning

confidence: 99%

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

Srivastava

Cao

Nedeva

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…However, recent studies suggest that topoisomerase I may not be the only target of irinotecan. The active metabolite of irinotecan, ethyl-10-hydroxy-camptothecin (SN38), interacts with the mouse double minute 2 homolog (MDM2) protein involved in TP53-mediated cell death and anti-apoptotic Bcl-2-like protein 1 isoform protein (BCL-xL) [ 43 ]. SN-38 was also shown to induce both cellular tumor antigen p53 ( TP53 ) expression and phosphorylation, which is accompanied with a concomitant elevated expression of downstream apoptosis-inducing proteins such as apoptosis regulator (BAX), caspase-3, and caspase-9 in human hepatocellular carcinoma cells in vitro.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Kciuk

Marciniak

Kontek

2020

IJMS

115

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Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan’s molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells’ resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.

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“…Alternatively, CPT‐11 itself potentially contributes to the synergistic effect. NMR analysis revealed that CPT‐11 directly binds to MDM2 and blocks MDM2‐p53 interaction [38]. As speculated, CPT‐11 alone induced a slight, but not negligible, level of p53 accumulation in H28 and 211H cells (Fig.…”

Section: Discussionmentioning

confidence: 84%

Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells

et al. 2020

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Malignant mesothelioma (MM) is an aggressive malignant neoplasm which rapidly invades pleural tissues and has a poor prognosis. Here, we explore enhancement of the effect of irinotecan [camptothecin-11 (CPT-11)] by the p53-dependent induction of carboxylesterase 2 (CES2), a CPT-11-activating enzyme, in MM. The level of CES2 mRNA was greatly increased on treatment with nutlin-3a. A combination of CPT-11 and nutlin-3a inhibited the growth of MM cells more effectively than either drug alone. Knocking down CES2 in MM cells reduced the effect of the drug combination, and its forced expression in MESO4 cells enhanced the growth inhibitory activity of CPT-11 in the absence of nutlin-3a. Enhancement of the growth inhibitory activity of CPT-11 by nutlin-3a suggests a possible new combinatorial MM chemotherapy regimen. Malignant mesotheliomas (MMs) are rare fatal malignancies associated with the exposure to asbestos, con-stituting~0.2% of all newly diagnosed malignancies [1]. MMs originate from mesothelial cells and fall into three main subtypes, epithelioid, sarcomatoid, and biphasic, according to the histological phenotype [2]. MMs of the sarcomatoid subtype have an exceptionally poor prognosis [3]. Most MM patients have unresectable disease, and therefore, different anticancer drug regimens have been tested in clinical trials.

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A novel mechanism of irinotecan targeting MDM2 and Bcl-xL

Cited by 17 publications

References 21 publications

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells

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