Hematologic malignancies: newer strategies to counter the BCL-2 protein

Ebrahim, Abdul Shukkur; Sabbagh, Hussam; Liddane, Allison; Raufi, Ali; Kandouz, Mustapha; Al‐Katib, Ayad

doi:10.1007/s00432-016-2144-1

Cited by 48 publications

(31 citation statements)

References 71 publications

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“…23 Bcl-2, an antiapoptotic member of the Bcl-2 family, is regarded as an oncogene capable of inducing various types of cancer. 24 Bax is a protein encoded in higher eukaryotes that control the death of cells by apoptosis. 25 Bad is an apoptotic protein from the Bcl-2 family and its inhibition plays an inhibitory role in the survival of breast cancer stem cells.…”

Section: Discussionmentioning

confidence: 99%

<p>Demethylation of the Cosmc Promoter Alleviates the Progression of Breast Cancer Through Downregulation of the Tn and Sialyl-Tn Antigens</p>

Wang

Cui

et al. 2020

CMAR

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These authors contributed equally to this workBackground: Aberrant gene methylation in breast cancer is associated with an unfavorable prognosis. Besides, abnormal Cosmc can induce the expression of Tn and STn antigens. The present study aimed to investigate the roles of Cosmc promoter methylation in breast cancer through the regulation of Tn and STn antigens. Methods: The expression patterns of Cosmc and the Tn and STn antigens in breast cancer cell lines were determined. Cosmc was overexpressed to explore the effects of Cosmc on cell behavior, including the growth, migration, invasion, and apoptosis of breast cancer cells and tumor growth with in vitro and in vivo experiments. Afterwards, a methyltransferase and a methyltransferase inhibitor were used to alter the methylation status of Cosmc to explore the mechanisms related to Cosmc promoter methylation. Results: Cosmc was poorly expressed in breast cancer cells. Cosmc overexpression inhibited cell growth, migration, and invasion while promoting apoptosis in breast cancer cells in vitro and restraining tumor growth in vivo. Cosmc promoter methylation was found to decrease the levels of Cosmc and increased the expression of the Tn and STn antigens in breast cancer. Conclusion: In conclusion, the demethylation of Cosmc mitigates breast cancer progression through the repression of the Tn and STn antigens, which provides evidence for therapeutic considerations for a novel target against breast cancer.

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Section: Discussionmentioning

confidence: 99%

<p>Demethylation of the Cosmc Promoter Alleviates the Progression of Breast Cancer Through Downregulation of the Tn and Sialyl-Tn Antigens</p>

Wang

Cui

et al. 2020

CMAR

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“… 9 A significant decrease in cell viability was observed after 48 hours in all of the cell lines exposed to PNT2258 at the lowest concentration (2.5 μM). 9 , 17 Nevertheless, PNT2258 has additional effects on WSU-FSCCL cells, such as cell cycle arrest, that cannot be explained by BCL-2 targeting. 18 Results of the present study suggest a broader mechanism of action for DNAi targeting both intended ( BCL-2 ) and unintended ( CDK4 ) genes.…”

Section: Discussionmentioning

confidence: 99%

Unintended target effect of anti-BCL-2 DNAi

Ebrahim

Kandouz²,

Emara

et al. 2017

CMAR

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IntroductionPrevious research suggested that a novel compound PNT2258 inhibits B-cell lymphoma 2 (BCL-2) transcription by DNA interference (DNAi) and demonstrated its activity in preclinical xenograft models and in a pilot Phase II clinical trial in non-Hodgkin’s lymphoma (NHL). While the drug downregulates BCL-2 at the promoter, mRNA, and protein levels, there is a significant homology (13–16 bases) between PNT100 and a number of promoters of genes involved in cell cycle regulation and survival. In this study, we identify cyclin-dependent kinase-4 (CDK4) as an unintended target gene of PNT2258 and examine its relevance to NHL.MethodsWe performed a Basic Local Alignment Search Tool (BLAST) homology search using PNT100 DNAi sequences. Also, we conducted CDK4 promoter assay in K562 cells and studied the protein expression of CDK4 in Wayne State University (WSU)-follicular small cleaved cell lymphoma (FSCCL), WSU-diffuse large cell lymphoma, and WSU-Waldenström’s macroglobulinemia (WM) lymphoma cells.ResultsBLAST homology search showed that PNT100 completely binds to BCL-2 gene as expected. However, there was 100% homology in a stretch of 14 bases (8–21) between PNT100 and CDK4. PNT2258 strongly inhibited CDK4 promoter activity in K562 cells. Moreover, CDK4 protein expression was significantly downregulated by PNT2258 in WSU-FSCCL and WSU-WM cell lines.DiscussionDNAi may work not only through knocking down the intended gene but also by knocking down other genes. PNT2258 affects CDK4 expression and promoter activity. Results of the present study suggest a broader mechanism of action for DNAi targeting both intended (BCL-2) and unintended (CDK4) genes.

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“…Additionally, BH3 profiling was developed in and has immense potential in the current era of BH3 mimetics. However, it is not clear if this technology will also help predict benefit to other anti-BCL-2 therapies such as interference strategies [168].…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer

Ngoi

Choong

Lee

et al. 2020

Cancers

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Deregulated cellular apoptosis is a hallmark of cancer and chemotherapy resistance. The B-cell lymphoma 2 (BCL-2) protein family members are sentinel molecules that regulate the mitochondrial apoptosis machinery and arbitrate cell fate through a delicate balance between pro- and anti-apoptotic factors. The recognition of the anti-apoptotic BCL2 gene as an oncogenic driver in hematological malignancies has directed attention toward unraveling the biological significance of each of the BCL-2 superfamily members in cancer progression and garnered interest in the targeting of apoptosis in cancer therapy. Accordingly, the approval of venetoclax (ABT-199), a small molecule BCL-2 inhibitor, in patients with chronic lymphocytic leukemia and acute myeloid leukemia has become the proverbial torchbearer for novel candidate drug approaches selectively targeting the BCL-2 superfamily. Despite the inspiring advances in this field, much remains to be learned regarding the optimal therapeutic context for BCL-2 targeting. Functional assays, such as through BH3 profiling, may facilitate prediction of treatment response, development of drug resistance and shed light on rational combinations of BCL-2 inhibitors with other branches of cancer therapy. This review summarizes the pathological roles of the BCL-2 family members in cancer, discusses the current landscape of their targeting in clinical practice, and highlights the potential for future therapeutic inroads in this important area.

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Hematologic malignancies: newer strategies to counter the BCL-2 protein

Cited by 48 publications

References 71 publications

<p>Demethylation of the Cosmc Promoter Alleviates the Progression of Breast Cancer Through Downregulation of the Tn and Sialyl-Tn Antigens</p>

<p>Demethylation of the Cosmc Promoter Alleviates the Progression of Breast Cancer Through Downregulation of the Tn and Sialyl-Tn Antigens</p>

Unintended target effect of anti-BCL-2 DNAi

Targeting Mitochondrial Apoptosis to Overcome Treatment Resistance in Cancer

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