HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells

Chen, Shu Huey; Chow, Jyh Ming; Hsieh, Yao Yu; Lin, Chun Yuan; Hsu, Kai-Wen; Hsieh, Wen Shyang; Ming, Wei; Shabangu, Beished M.; Lee, Chia Hwa

doi:10.3390/ijms20092271

Cited by 23 publications

(21 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, at these concentrations, imatinib significantly inhibited K562 cell viability and cell proliferation by approximately 50% compared to the DMSO control, whereas only sgRNA_2 virus infection had a similar inhibitory effect on K562 cell viability ( Figure 7 E, p < 0.05). Our recent study showed that imatinib-resistant K562 cells (K562-IR) have a much higher IC50 value for imatinib treatment than wild-type K562 cells, with a 30-fold increase in drug sensitivity [ 25 ]. With the same cells, we did not find any mutations in the entire ABL gene through Sanger sequencing, indicating that BCR-ABL amino acid substitutions inside the kinase domain may not be the main cause of disruption in the interaction of imatinib and the tyrosine kinase domain, resulting in a loss of sensitivity to the drug in our long-term imatinib-treated K562-IR cells.…”

Section: Resultsmentioning

confidence: 99%

ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo

Chen

Hsieh

Tzeng

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Chronic myelogenous leukemia (CML) is the most common type of leukemia in adults, and more than 90% of CML patients harbor the abnormal Philadelphia chromosome (Ph) that encodes the BCR-ABL oncoprotein. Although the ABL kinase inhibitor (imatinib) has proven to be very effective in achieving high remission rates and improving prognosis, up to 33% of CML patients still cannot achieve an optimal response. Here, we used CRISPR/Cas9 to specifically target the BCR-ABL junction region in K562 cells, resulting in the inhibition of cancer cell growth and oncogenesis. Due to the variety of BCR-ABL junctions in CML patients, we utilized gene editing of the human ABL gene for clinical applications. Using the ABL gene-edited virus in K562 cells, we detected 41.2% indels in ABL sgRNA_2-infected cells. The ABL-edited cells reveled significant suppression of BCR-ABL protein expression and downstream signals, inhibiting cell growth and increasing cell apoptosis. Next, we introduced the ABL gene-edited virus into a systemic K562 leukemia xenograft mouse model, and bioluminescence imaging of the mice showed a significant reduction in the leukemia cell population in ABL-targeted mice, compared to the scramble sgRNA virus-injected mice. In CML cells from clinical samples, infection with the ABL gene-edited virus resulted in more than 30.9% indels and significant cancer cell death. Notably, no off-target effects or bone marrow cell suppression was found using the ABL gene-edited virus, ensuring both user safety and treatment efficacy. This study demonstrated the critical role of the ABL gene in maintaining CML cell survival and tumorigenicity in vitro and in vivo. ABL gene editing-based therapy might provide a potential strategy for imatinib-insensitive or resistant CML patients.

show abstract

Section: Resultsmentioning

confidence: 99%

ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo

Chen

Hsieh

Tzeng

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…Notably, in silico predictions should be critically considered due to potentially different pharmacokinetic properties of compounds in vivo. Collectively, MAKV-8 appears to be an attractive drug candidate for further consideration in CML therapies, especially considering that the inhibition of HDAC1 and HDAC2, upregulated in LSCs versus HSCs from patients, strongly impacts the transcription of proteins essential for tumor cell survival [21].…”

Section: Discussionmentioning

confidence: 99%

“…8a). The importance of HDAC1 and HDAC2 in tumor cell survival provides a good rational for treating CML cells with imatinib in combination with pan-HDACis [21].…”

Section: Modulation Of Hdac Expression Profiles In CML Patientsmentioning

confidence: 99%

Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells

et al. 2020

View full text Add to dashboard Cite

Background: Chronic myeloid leukemia (CML) pathogenesis is mainly driven by the oncogenic breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) fusion protein. Since BCR-ABL displays abnormal constitutive tyrosine kinase activity, therapies using tyrosine kinase inhibitors (TKis) such as imatinib represent a major breakthrough for the outcome of CML patients. Nevertheless, the development of TKi resistance and the persistence of leukemia stem cells (LSCs) remain barriers to cure the disease, justifying the development of novel therapeutic approaches. Since the activity of histone deacetylase (HDAC) is deregulated in numerous cancers including CML, pan-HDAC inhibitors may represent promising therapeutic regimens for the treatment of CML cells in combination with TKi. Results: We assessed the anti-leukemic activity of a novel hydroxamate-based pan-HDAC inhibitor MAKV-8, which complied with the Lipinski's "rule of five," in various CML cells alone or in combination with imatinib. We validated the in vitro HDAC-inhibitory potential of MAKV-8 and demonstrated efficient binding to the ligand-binding pocket of HDAC isoenzymes. In cellulo, MAKV-8 significantly induced target protein acetylation, displayed cytostatic and cytotoxic properties, and triggered concomitant ER stress/protective autophagy leading to canonical caspase-dependent apoptosis. Considering the specific upregulation of selected HDACs in LSCs from CML patients, we investigated the differential toxicity of a co-treatment with MAKV-8 and imatinib in CML versus healthy cells. We also showed that beclin-1 knockdown prevented MAKV-8-imatinib combination-induced apoptosis. Moreover, MAKV-8 and imatinib cotreatment synergistically reduced BCR-ABL-related signaling pathways involved in CML cell growth and survival. Since our results showed that LSCs from CML patients overexpressed c-MYC, importantly MAKV-8-imatinib co-treatment reduced c-MYC levels and the LSC population. In vivo, tumor growth of xenografted K-562 cells in zebrafish was completely abrogated upon combined treatment with MAKV-8 and imatinib.

show abstract

“…Interestingly, several members of the HDAC family are implicated in the development/maintenance of cancer stemness and fulfilment of the EMT program, while some HDAC inhibitors are suggested to be used against CSCs [ 338 , 339 ]. If HDAC inhibitors are capable of suppressing the EMT-associated generation of radioresistant and actively migrating CSC-like cells in hypoxic niches, such agents may sensitize hypoxic tumors to radiotherapy.…”

Section: How Do Epigenetic Regulators Affect the Radioresistance Omentioning

confidence: 99%

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Kabakov

Yakimova

2021

Cancers

View full text Add to dashboard Cite

Within aggressive malignancies, there usually are the “hypoxic zones”—poorly vascularized regions where tumor cells undergo oxygen deficiency through inadequate blood supply. Besides, hypoxia may arise in tumors as a result of antiangiogenic therapy or transarterial embolization. Adapting to hypoxia, tumor cells acquire a hypoxia-resistant phenotype with the characteristic alterations in signaling, gene expression and metabolism. Both the lack of oxygen by itself and the hypoxia-responsive phenotypic modulations render tumor cells more radioresistant, so that hypoxic tumors are a serious challenge for radiotherapy. An understanding of causes of the radioresistance of hypoxic tumors would help to develop novel ways for overcoming this challenge. Molecular targets for and various approaches to radiosensitizing hypoxic tumors are considered in the present review. It is here analyzed how the hypoxia-induced cellular responses involving hypoxia-inducible factor-1, heat shock transcription factor 1, heat shock proteins, glucose-regulated proteins, epigenetic regulators, autophagy, energy metabolism reprogramming, epithelial–mesenchymal transition and exosome generation contribute to the radioresistance of hypoxic tumors or may be inhibited for attenuating this radioresistance. The pretreatments with a multitarget inhibition of the cancer cell adaptation to hypoxia seem to be a promising approach to sensitizing hypoxic carcinomas, gliomas, lymphomas, sarcomas to radiotherapy and, also, liver tumors to radioembolization.

show abstract

HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells

Cited by 23 publications

References 28 publications

ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo

ABL Genomic Editing Sufficiently Abolishes Oncogenesis of Human Chronic Myeloid Leukemia Cells In Vitro and In Vivo

Novel HDAC inhibitor MAKV-8 and imatinib synergistically kill chronic myeloid leukemia cells via inhibition of BCR-ABL/MYC-signaling: effect on imatinib resistance and stem cells

Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing

Contact Info

Product

Resources

About