MiRNA-Mediated Knock-Down of Bcl-2 and Mcl-1 Increases Fludarabine-Sensitivity in CLL-CII Cells

Ashofteh, Nooshin; Amini, Razieh; Molaee, Neda; Karami, Hadi; Baazm, Maryam

doi:10.31557/apjcp.2021.22.7.2191

Cited by 8 publications

(5 citation statements)

References 25 publications

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“…Inhibition of Mcl-1 has been found to sensitize AML cells and AML stem/progenitor cells, including those that are intrinsically and acquiredly resistant to venetoclax, through the cooperative release of proapoptotic Bcl-2 interacting mediator of cell death , Bcl-2-associated X protein and Bcl-2 homologous antagonist/killer from antiapoptotic Bcl-2 proteins [19]. Depletion of both Bcl-2 and Mcl-1 has been shown to increase fludarabine sensitivity in chronic lymphocytic leukemia cells [20]. Targeting cancer stem cells with a pan-Bcl-2 inhibitor has been found to overcome resistance in both preclinical and clinical settings in patients with gastroesophageal carcinoma [21].…”

Section: Discussionmentioning

confidence: 99%

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer

Wang,

Xi,

Liu

et al. 2023

Anti-Cancer Drugs

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After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer

Wang,

Xi,

Liu

et al. 2023

Anti-Cancer Drugs

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“…The RT-qPCR condition was 95 o C for 10 min followed by 35 cycles at 95oC for 20 sec and 60 o C for 1 min. Relative gene expression was determined with the 2 -(ΔΔCt) method [13,14], using β-actin as an internal control.…”

Section: Rt-qpcrmentioning

confidence: 99%

The Effects of ABT-199 and Dihydroartemisinin Combination on Cell Growth and Apoptosis in Human U937 and KG-1 Cancer Cells

Nazmabadi,

Pooladi,

Amri

et al. 2024

Asian Pac J Cancer Prev

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Introduction: Change in the balance of Bcl-2 family proteins is one of the main reasons for resistance of tumor cells to ABT-199. In this study, the effect of dihydroartemisinin on cell growth, apoptosis and sensitivity of the AML cells to ABT-199 was investigated. Methods: Cell proliferation and survival were assessed by trypan blue staining and MTT assay, respectively. Cell apoptosis was measured by Hoechst 33342 staining and caspase-3 activity assay. The expression levels of Bcl-2, Mcl-1 and Bax mRNA were tested by qRT-PCR. Results: Our data showed that combination therapy significantly reduced the IC 50 value and synergistically decreased the AML cell survival and growth compared with dihydroartemisinin or ABT-199 alone. Treatment with each of ABT-199 or dihydroartemisinin alone clearly enhanced the Bax mRNA expression and inhibited the expression of Mcl-1 and Bcl-2 mRNA. Inhibition of Mcl-1 mRNA by dihydroartemisinin was associated with enhancement of apoptosis induced by ABT-199 in AML cells. Conclusion: In conclusion, dihydroartemisinin not only triggers the intrinsic pathway of apoptosis, but also can increase the sensitivity of the AML cells to ABT-199 via suppression of Mcl-1 expression.

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“…The initial denaturation qRT-PCR step at 95˚C for 10 min was followed by 35 cycles at 95˚C for 20 sec and 60˚C for 1 min. The relative expression level of mRNA was analyzed with the 2 -(ΔΔCt) method [19,20], by using β-actin as an endogenous control gene.…”

Section: Qrt-pcrmentioning

confidence: 99%

Dihydroartemisinin Enhances the Therapeutic Efficacy of BH3 Mimetic Inhibitor in Acute Lymphoblastic Leukemia Cells via Inhibition of Mcl-1

Nazmabadi,

Pooladi,

Amri

et al. 2024

Asian Pac J Cancer Prev

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Introduction: Up-regulation of the anti-apoptotic proteins such as Mcl-1 is associated with the primary and secondary resistance of tumor cells to ABT-737 Bcl-2 inhibitor. The combined treatment of Bcl-2 inhibitors with Mcl-1 inhibitors has been proposed as an attractive therapeutic strategy to overcome this drug resistance. Here, we investigated the effect of dihydroartemisinin on Mcl-1 expression and sensitization of T-ALL cells to ABT-737. Methods: The cell growth and survival were tested by the cell proliferation and MTT assays, respectively. The mRNA levels of Bcl-2, Mcl-1, Bax and P21 were examined by qRT-PCR. Apoptosis were detected by Hoechst 33342 staining and caspase-3 activity assay. Results: Our data showed that combination treatment with dihydroartemisinin and ABT-737 caused a significant decrease in the IC 50 value and synergistically reduced the cell survival compared with dihydroartemisinin or ABT-737 alone. ABT-737 enhanced the Mcl-1 mRNA expression. Dihydroartemisinin also down-regulated the expression of Bcl-2 and Mcl-1 and enhanced the P21 and Bax expression. Moreover, dihydroartemisinin enhanced the apoptosis induced by ABT-737 in MOLT-4 and MOLT-17 cell lines. Conclusion: In conclusion, dihydroartemisinin demonstrates anti-tumor activities in human ALL cells via inhibition of cell survival and growth. Dihydroartemisinin augments the apoptotic effect of ABT-737 by inhibiting the expression of Mcl-1.

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MiRNA-Mediated Knock-Down of Bcl-2 and Mcl-1 Increases Fludarabine-Sensitivity in CLL-CII Cells

Cited by 8 publications

References 25 publications

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer

Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer

The Effects of ABT-199 and Dihydroartemisinin Combination on Cell Growth and Apoptosis in Human U937 and KG-1 Cancer Cells

Dihydroartemisinin Enhances the Therapeutic Efficacy of BH3 Mimetic Inhibitor in Acute Lymphoblastic Leukemia Cells via Inhibition of Mcl-1

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