Entinostat combined with Fludarabine synergistically enhances the induction of apoptosis in TP53 mutated CLL cells via the HDAC1/HO-1 pathway

Zhou, Zhen; Fang, Qin; Li, Peifan; Ma, Dan; Zhe, Nana; Ren, Mei; Chen, Bingqing; He, Zhengchang; Wang, Jun; Wang, Jishi

doi:10.1016/j.lfs.2019.116583

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…Fludarabine, a chemotherapeutic drug used in the treatment of a small subset of CLL patients alone or in combination with other chemotherapeutic or immunomodulatory drugs, enhances Bax activation and expression and promotes apoptosis of CLL cells ( 9 , 10 ). We tested whether, similar to Venetoclax, the combination of GroPIns with Fludarabine further enhances Fludarabine-induced CLL cell apoptosis.…”

Section: Resultsmentioning

confidence: 99%

“…The expression of Bax is profoundly impaired in CLL cells ( 2 ), which contributes to their apoptosis defects. A number of drugs currently in clinical use for the treatment of several types of cancer are known to indirectly enhance Bax expression and activation, including Fludarabine ( 9 , 10 ) and Venetoclax ( 40 ). Here we demonstrate that GroPIns promotes CLL cell apoptosis by enhancing Bax expression.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore not surprising that restoring the Bcl-2 family balance has been pinpointed as strategy for overcoming the apoptosis defects of CLL cells, as witnessed by the recent approval of the Bcl-2 selective inhibitor Venetoclax for CLL treatment ( 7 , 8 ). This effect is also elicited by chemotherapeutic drugs such as the fluorinated nucleotide analog Fludarabine, which affects the Bcl-2 family balance by indirectly promoting both expression and activation of Bax ( 9 , 10 ). As opposed to Bcl-2, no drugs that specifically target Bax to enhance its expression or activation have been as yet developed ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

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Glycerophosphoinositol Promotes Apoptosis of Chronic Lymphocytic Leukemia Cells by Enhancing Bax Expression and Activation

et al. 2022

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An imbalance in the expression of pro- and anti-apoptotic members of the Bcl-2 family of apoptosis-regulating proteins is one of the main biological features of CLL, highlighting these proteins as therapeutic targets for treatment of this malignancy. Indeed, the Bcl-2 inhibitor Venetoclax is currently used for both first-line treatment and treatment of relapsed or refractory CLL. An alternative avenue is the transcriptional modulation of Bcl-2 family members to tilt their balance towards apoptosis. Glycerophosphoinositol (GroPIns) is a biomolecule generated from membrane phosphoinositides by the enzymes phospholipase A2 and lysolipase that pleiotropically affects key cellular functions. Mass-spectrometry analysis of GroPIns interactors recently highlighted the ability of GroPIns to bind to the non-receptor tyrosine phosphatase SHP-1, a known promoter of Bax expression, suggesting that GroPIns might correct the Bax expression defect in CLL cells, thereby promoting their apoptotic demise. To test this hypothesis, we cultured CLL cells in the presence of GroPIns, alone or in combination with drugs commonly used for treatment of CLL. We found that GroPIns alone increases Bax expression and apoptosis in CLL cells and enhances the pro-apoptotic activity of drugs used for CLL treatment in a SHP-1 dependent manner. Interestingly, among GroPIns interactors we found Bax itself. Short-term treatments of CLL cells with GroPIns induce Bax activation and translocation to the mitochondria. Moreover, GroPIns enhances the pro-apoptotic activity of Venetoclax and Fludarabine in CLL cells. These data provide evidence that GroPIns exploits two different pathways converging on Bax to promote apoptosis of leukemic cells and pave the way to new studies aimed at testing GroPIns in combination therapies for the treatment of CLL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glycerophosphoinositol Promotes Apoptosis of Chronic Lymphocytic Leukemia Cells by Enhancing Bax Expression and Activation

et al. 2022

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“…In addition, silencing of HO-1 significantly enhanced the sensitivity of HL-60R AML cell line to chemotherapy (Zhe et al 2015) and induced apoptosis and cell growth arrest in acute lymphocytic leukemia (Cerny-Reiterer et al 2014) as well as in chronic lymphocytic leukemia, where the silencing also enhanced the effects of the combined therapy fludarabine plus entinostat (Zhou et al 2019).…”

Section: :1 E230006mentioning

confidence: 97%

Role of heme oxygenase-1 in tumor immune escape

Nitti

Ortolan

Furfaro

2023

Redox Experimental Medicine

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The inducible enzyme heme oxygenase 1 (HO-1) plays a pivotal role in cell defense against different kind of stressors, from oxidative stress to hypoxia. For this reason, HO-1 overexpression has been correlated to cancer aggressiveness in different tumors, being one of the molecular mechanisms used by tumor cells to become resistant to therapies. In addition, HO-1 has a well-recognized role in restraining immune response and in maintaining tolerance. In this context, the possibility that HO-1 induction in immune cells can reduce immune response to cancer and impair cancer immune therapy becomes a hot topic in cancer research. In this review, the most recent evidence pointing out the role of HO-1 in generating a permissive tumor microenvironment has been discussed as well as the most promising therapeutic approaches to increase effectiveness of immune therapies.

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“…Furthermore, HO-1 is considered a survival factor in ALL, regardless of Philadelphia chromosome positivity; indeed, the down-regulation of HO-1 expression by siRNA increases apoptosis and arrests cell growth [ 219 ]. Consistently, in chronic lymphocytic leukemia (CLL), it has been demonstrated that HO-1 silencing directly leads to apoptosis of MEC-1 cells and enhances the effects of the combined therapy fludarabine plus entinostat [ 220 ].…”

Section: Ho-1 and Tumor Therapiesmentioning

confidence: 99%

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

et al. 2021

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Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

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Entinostat combined with Fludarabine synergistically enhances the induction of apoptosis in TP53 mutated CLL cells via the HDAC1/HO-1 pathway

Cited by 5 publications

References 52 publications

Glycerophosphoinositol Promotes Apoptosis of Chronic Lymphocytic Leukemia Cells by Enhancing Bax Expression and Activation

Glycerophosphoinositol Promotes Apoptosis of Chronic Lymphocytic Leukemia Cells by Enhancing Bax Expression and Activation

Role of heme oxygenase-1 in tumor immune escape

Clinical Significance of Heme Oxygenase 1 in Tumor Progression

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