Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia

Sun, Wen Tian; Xiang, Wei; Ng, Bee Ling; Asari, Kartini; Bunte, Ralph M.; Casey, Patrick J.; Wang, Mei; Chuah, Charles

doi:10.1016/j.exphem.2015.12.002

Cited by 11 publications

(5 citation statements)

References 18 publications

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“…7b and e). This is consistent with our previous work and others, possibly due to a compensatory response to inhibition of Bcr-Abl kinase activity [34,35].…”

Section: Resultssupporting

confidence: 94%

Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation

et al. 2021

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The resistance of chronic myeloid leukaemia (CML) to tyrosine kinase inhibitors (TKIs) remains a significant clinical problem. Targeting alternative pathways, such as protein prenylation, is known to be effective in overcoming resistance. Simvastatin inhibits 3-hydroxy-3-methylglutaryl-CoA reductase (a key enzyme in isoprenoid-regulation), thereby inhibiting prenylation. We demonstrate that simvastatin alone effectively inhibits proliferation in a panel of TKI-resistant CML cell lines, regardless of mechanism of resistance. We further show that the combination of nilotinib and simvastatin synergistically kills CML cells via an increase in apoptosis and decrease in prosurvival proteins and cellular proliferation. Mechanistically, simvastatin inhibits protein prenylation as shown by increased levels of unprenylated Ras and rescue experiments with mevalonate resulted in abrogation of synergism. The combination also leads to an increase in the intracellular uptake and retention of radiolabelled nilotinib, which further enhances the inhibition of Bcr-Abl kinase activity. In primary CML samples, this combination inhibits clonogenicity in both imatinib-naive and resistant cells. Such combinatorial effects provide the basis for utilising these Food and Drug Administrationapproved drugs as a potential clinical approach in overcoming resistance and improving CML treatment.

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“…7b and e). This is consistent with our previous work and others, possibly due to a compensatory response to inhibition of Bcr-Abl kinase activity [34,35].…”

Section: Resultssupporting

confidence: 94%

Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation

et al. 2021

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“…Cysmethynil was also found to mitigate the disease phenotype in two malignant pleural effusion models in mice [94]. In the study of hematologic malignancy, cysmethynil was found to enhance imatinib-induced apoptosis in chronic myeloid leukemia (CML) cells, both in vitro and in a mouse model, possibly via the inhibition of the MAPK/ERK pathway to enhance the therapeutic effects of imatinib [95].…”

Section: Developing Icmt Inhibitorsmentioning

confidence: 99%

Small change, big effect: Taking RAS by the tail through suppression of post-prenylation carboxylmethylation

Lau

Wang

2018

Small GTPases

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Mutant RAS isoforms are the most common oncogenes affecting human cancers. After decades of effort in developing drugs targeting oncogenic RAS-driven cancers, we are still charting an unclear path. Despite recent developments exemplified by KRAS (G12C) inhibitors, direct targeting of mutant RAS remains a difficult endeavor. Inhibiting RAS function by targeting its post-translational prenylation processing has remained an important approach, especially with recent progress on the study of isoprenylcysteine carboxylmethyltransferase (ICMT), the unique enzyme for the last step of prenylation processing of RAS isoforms and other substrates. Inhibition of ICMT has shown efficacy both in vitro and in vivo in RAS-mutant cancer models. We will discuss the roles of RAS family of proteins in human cancers and the impact of post-prenylation carboxylmethylation on RAS driven tumorigenesis. In addition, we will review what is known of the molecular and cellular impact of ICMT inhibition on cancer cells that underlie its anti-proliferative and pro-apoptosis efficacy.

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“…Recent studies have shown that the expression of ICMT is up-regulated in ovarian cancer and cervical cancer, and that it promotes a variety of malignant biological behaviors of tumor cells, such as growth, migration, and survival (6)(7)(8). Consistently, ICMT inhibition has exhibited anticancer activity in cancers including pancreatic cancer, leukemia, and cervical cancer (9)(10)(11).…”

Section: Introductionmentioning

confidence: 98%

Lidocaine exerts anticancer activity in bladder cancer by targeting isoprenylcysteine carboxylmethyltransferase (ICMT)

Teng¹,

Yang²,

Wang³

et al. 2021

Transl Androl Urol

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Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia

Cited by 11 publications

References 18 publications

Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation

Simvastatin enhances the efficacy of nilotinib in chronic myeloid leukaemia by post-translational modification and drug transporter modulation

Small change, big effect: Taking RAS by the tail through suppression of post-prenylation carboxylmethylation

Lidocaine exerts anticancer activity in bladder cancer by targeting isoprenylcysteine carboxylmethyltransferase (ICMT)

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