The ρ-kinase inhibitors Y-27632 and fasudil act synergistically with imatinib to inhibit the expansion of ex vivo CD34+ CML progenitor cells

Burthem, John; Mottram, Rachel; Adams, Julie A.; Lucas, Guy; Spooncer, Elaine; Whetton, Anthony D.

doi:10.1038/sj.leu.2404762

Cited by 36 publications

(32 citation statements)

References 24 publications

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“…Even though our data in additional primary AML donors are limited in number, they are well in line with data generated by other groups in CML. 23,42 Interestingly, both our data and 1 of the earlier reports in CML suggest that normal HSPCs are less sensitive to ROCK1 inhibition than leukemic blasts. These observations and the excellent tolerability of prolonged fasudil exposure in humans 43,44 and in our mouse model argue for the feasibility of repetitive dosing to increase peak serum levels observed after a single application of this drug 25 to levels needed for efficient ROCK1 inhibition in vivo.…”

Section: Discussionsupporting

confidence: 68%

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Wermke

Camgöz

Paszkowski‐Rogacz

et al. 2015

Blood

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Key Points• Large-scale loss-of-function RNAi screens in patientderived AML cells are feasible and able to pinpoint therapeutic targets.• ROCK1 inhibition exerts antileukemic effects in primary human AML cells in vitro and in vivo.Acute myeloid leukemia (AML) is characterized by a marked genetic heterogeneity, which complicates the development of novel therapeutics. The delineation of pathways essential within an individual patient's mutational background might overcome this limitation and facilitate personalized treatment. We report the results of a large-scale lentiviral lossof-function RNA interference (RNAi) screen in primary leukemic cells. Stringent validation identified 6 genes (BNIPL1, ROCK1, RPS13, STK3, SNX27, WDHD1) whose knockdown impaired growth and viability of the cells. Dependence on these genes was not caused by mutation or overexpression, and although some of the candidates seemed to be rather patient specific, others were essential in cells isolated from other AML patients. In addition to the phenotype observed after ROCK1 knockdown, treatment with the approved ROCK inhibitor fasudil resulted in increased apoptosis and decreased viability of primary AML cells. In contrast to observations in some other malignancies, ROCK1 inhibition did not foster growth of immature malignant progenitors but was toxic to this cell fraction in feeder coculture and xenotransplant experiments, indicating a distinct effect of ROCK1 inhibition on leukemic progenitors. We conclude that large-scale RNAi screens in primary patient-derived cells are feasible and can complement other methods for personalized cancer therapies, such as expression and mutation profiling. (Blood. 2015;125(24):3760-3768)

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Section: Discussionsupporting

confidence: 68%

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Wermke

Camgöz

Paszkowski‐Rogacz

et al. 2015

Blood

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“…A publication by Burthem and colleagues shows that ROCK inhibitors such as Y-27632 and fasudil combined with the TKI imatinib synergistically inhibits the activity of human leukemic cells [26]. These results show that ROCK may be a potential additional therapeutic target in impairing the oncogenic activity of TK-driven malignancies and validate the use of these inhibitors as either single agents or combined with other TKIs as a possible therapeutic strategy.…”

Section: Discussionmentioning

confidence: 80%

Combined inhibition of rho-associated protein kinase and EGFR suppresses the invasive phenotype in EGFR-dependent lung cancer cells

et al. 2015

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a b s t r a c tIntroduction: Lung cancer remains the leading cause of cancer-related mortality worldwide, with metastatic disease frequently a prominent feature at the time of diagnosis. The role of NSCLC-derived EGFR mutations in cancer cell proliferation and survival has been widely reported, but little is known about the function of these mutations in invasive growth and metastasis. In this study, we sought to evaluate the intrinsic invasive properties of NSCLC cells with differing EGFR status and examine possible therapeutic targets that can abrogate invasive growth. Materials and methods: Collagen-based assays and 3D cell cultures were used to assess morphological features, actin cytoskeleton dynamics and the invasive capacity of NSCLC cell lines with differing EGFR status. The role of the RhoA/ROCK/MYPT1 and EGFR/HER pathways in NSCLC-related invasion was investigated by pharmacological inhibition and RNA interference techniques. Results: We demonstrate a positive correlation between EGFR mutational/amplification status and invasive capacity. Knockdown of wild-type and mutant EGFR leads to depletion of active and total MYPT1 levels. Combined pharmacological inhibition or genetic ablation of ROCK/EGFR suppresses the hallmarks of cancer cells and abrogates the invasive phenotype in EGFR-dependent NSCLC cells. Conclusions: These observations suggest that combined targeting of the ROCK and EGFR/HER pathways may be a potential therapeutic approach in limiting invasive growth in NSCLC.

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“…Although most patients respond to first-line imatinib therapy, resistance (Volpe et al, 2009;Nair et al, 2012), toxicity (Faber et al, 2006) or intolerance has caused some patients to fail to respond to the standard dose. Thus, to optimize therapeutic benefit, physicians choose customized therapy based on each patient's historical response, adverse-event tolerance level, risk factors and the administration of anti-cancer herbal agents with low toxicity, which are attractive either alone or in combination with imatinib (Radujkovic et al, 2006;Walz and Sattler, 2006;Burthem et al, 2007;Murray-Rust and Rzepa, 2011;Agarwal et al, 2012). Shishodia et al reported that curcumin (isolated from the rhizome of the plant Curcuma longa) inhibited proliferation of primary CML cells and down-regulated STAT5 mRNA levels and activity (Shishodia et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

A derivative of epigallocatechin‐3‐gallate induces apoptosis via SHP‐1‐mediated suppression of BCR‐ABL and STAT3 signalling in chronic myelogenous leukaemia

Jung

Yun

Choo

et al. 2015

British J Pharmacology

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Background and PurposeEpigallocatechin‐3‐gallate (EGCG) is a component of green tea known to have chemo‐preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent.Experimental ApproachDerivatives of EGCG were evaluated for their stability and anti‐tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells.Key ResultsEGCG‐mono‐palmitate (EGCG‐MP) showed most prolonged stability compared with other EGCG derivatives. EGCG‐MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG‐MP induced Src‐homology 2 domain‐containing tyrosine phosphatase 1 (SHP‐1) leading decreased oncogenic protein BCR‐ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG‐MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP‐1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG‐MP to suppress phosphorylation of BCR‐ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG‐MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP‐1 activity and decreased phosphorylation of BCR‐ABL in the EGCG‐MP‐treated group relative to that in the EGCG‐treated group.Conclusions and ImplicationsEGCG‐MP induced SHP‐1‐mediated inhibition of BCR‐ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment.

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The ρ-kinase inhibitors Y-27632 and fasudil act synergistically with imatinib to inhibit the expansion of ex vivo CD34+ CML progenitor cells

Cited by 36 publications

References 24 publications

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

Combined inhibition of rho-associated protein kinase and EGFR suppresses the invasive phenotype in EGFR-dependent lung cancer cells

A derivative of epigallocatechin‐3‐gallate induces apoptosis via SHP‐1‐mediated suppression of BCR‐ABL and STAT3 signalling in chronic myelogenous leukaemia

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