It's time to die: BH3 mimetics in solid tumors

Kehr, Sarah; Vogler, Meike

doi:10.1016/j.bbamcr.2021.118987

Cited by 53 publications

(47 citation statements)

References 125 publications

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“…Apoptosis is strictly regulated in several cells and required activation or inhibition of several proteins involved in programmed cell death. Bcl-2 acts as an anti-apoptotic protein by inhibiting other pro-apoptotic proteins (Senichkin et al, 2020;Kehr and Vogler, 2021). DENV infection in MEG-01 cells showed a reduction of Bcl-2 that also supports our finding of apoptosis in megakaryocytes.…”

Section: Discussionsupporting

confidence: 90%

“…So far, we have observed that DENV infection is impairing the PI3K/AKT/mTOR axis in MEG-01 cells, which may activate molecules responsible for cell death/apoptosis. Bcl-2 is an antiapoptotic protein that keeps other apoptotic proteins in inactive form and inhibits apoptosis (Senichkin et al, 2020;Kehr and Vogler, 2021). Immunoblotting of Bcl-2 was carried out on previously explained conditions.…”

Section: Expression Of Pro and Anti-apoptotic Markers In Denv Infected Megakaryocytesmentioning

confidence: 99%

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Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

Lahon

Arya

Banerjea

2021

Front. Cell. Infect. Microbiol.

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Dengue virus (DENV) infection can cause either self-limited dengue fever or hemorrhagic complications. Low platelet count is one of the manifestations of dengue fever. Megakaryocytes are the sole producers of platelets. However, the role of both host and viral factors in megakaryocyte development, maturation, and platelet production is largely unknown in DENV infection. PI3K/AKT/mTOR pathway plays a significant role in cell survival, maturation, and megakaryocyte development. We were interested to check whether pathogenic insult can impact this pathway. We observed decreased expression of most of the major key molecules associated with the PI3K/AKT/mTOR pathway in DENV infected MEG-01 cells. In this study, the involvement of PI3K/AKT/mTOR pathway in megakaryocyte development and maturation was confirmed with the use of specific inhibitors in infected MEG-01 cells. Our results showed that direct pharmacologic inhibition of this pathway greatly impacted megakaryopoiesis associated molecule CD61 and some essential transcription factors (GATA-1, GATA-2, and NF-E2). Additionally, we observed apoptosis in megakaryocytes due to DENV infection. Our results may suggest that DENV impairs PI3K/AKT/mTOR axis and molecules involved in the development and maturation of megakaryocytes. It is imperative to investigate the role of these molecules in the context of megakaryopoiesis during DENV infection to better understand the pathways and mechanisms, which in turn might provide insights into the development of antiviral strategies.

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Section: Discussionsupporting

confidence: 90%

Section: Expression Of Pro and Anti-apoptotic Markers In Denv Infected Megakaryocytesmentioning

confidence: 99%

Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

Lahon

Arya

Banerjea

2021

Front. Cell. Infect. Microbiol.

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“…Moreover, combination of S63845 and A-1331852 inhibited spheroid growth and invasion at low doses, indicating that the combination may be effective in vivo. In accordance with our study findings, many solid tumours are dependent on BCL-XL and MCL-1 for survival [11]. However, targeting BCL-XL and MCL-1 in the clinic may be cumbersome.…”

Section: Discussionsupporting

confidence: 92%

Dual inhibition of anti-apoptotic proteins BCL-XL and MCL-1 enhances cytotoxicity of Nasopharyngeal carcinoma cells

Rahman

Azlan

et al. 2021

Preprint

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One of the many strategies that cancer cells use to evade cell death is through upregulation of the BCL-2 anti-apoptotic proteins. Hence, these proteins have become attractive therapeutic targets. Given that different cell population rely on different anti-apoptotic proteins for survival, it is crucial to determine which proteins are important for NPC survival. Here we determined the survival requirements for the NPC cells using combination of CRISPR/Cas9 technique and pharmacological approaches. A human apoptosis RT2 Profiler PCR Array was first employed to profile the anti-apoptotic gene expressions in NPC cell lines HK-1 and C666-1. The HK-1 cells expressed all the anti-apoptotic genes (MCL-1, BFL-1, BCL-2, BCL-XL, and BCL-w). Similarly, the C666-1 cells expressed all the anti-apoptotic proteins except BFL-1 (undetectable level). Notably, both cell lines highly expressed MCL-1. Deletion of MCL-1 sensitized cells to A-1331852 suggesting that MCL-1 and BCL-XL may be important for NPC cell survival. Co-inhibition of MCL-1 and BCL-2 with MCL-1 selective inhibitor S63845 and BCL-2 selective inhibitor ABT-199 inhibited NPC cell proliferation but the effect on cell viability was more profound with co-inhibition of MCL-1 and BCL-XL with S63845 and A-1331852, implying that MCL-1 and BCL-XL are crucial for NPC cell survival. Furthermore, co-inhibition of MCL-1 and BCL-XL inhibited the growth and invasion of NPC spheroids. Deletion of BFL-1 sensitized cells to A-1331852 suggesting that BFL-1 may play a role in NPC cell survival. Taken together co-inhibition of BCL-XL and MCL-1/BFL-1 could be potential treatment strategies for NPC.

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“…UBX1325 (Unity Biotechnology, San Franscisco, CA, USA), another specific BCL- X L inhibitor, is also being evaluated in patients with diabetic macular edema widening the scope of this class of agents beyond cancer (NCT04537884, NCT04857996). An alternative approach using a BCL-X L targeting antibody drug conjugate (ABBV-155, AbbVie, North Chicago, IL, USA), is currently being evaluated in a phase I trial as monotherapy and in combination with docetaxel or paclitaxel for small cell lung cancer, NSCLC, and breast cancer (NCT03595059) [ 51 , 52 ].…”

Section: Therapeutic Strategies For Promoting Apoptosis Directly—intrinsic Pathwaymentioning

confidence: 99%

Therapeutics Targeting the Core Apoptotic Machinery

Hamilton

Fox

Longley

et al. 2021

Cancers

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Therapeutic targeting of the apoptotic pathways for the treatment of cancer is emerging as a valid and exciting approach in anti-cancer therapeutics. Accumulating evidence demonstrates that cancer cells are typically “addicted” to a small number of anti-apoptotic proteins for their survival, and direct targeting of these proteins could provide valuable approaches for directly killing cancer cells. Several approaches and agents are in clinical development targeting either the intrinsic mitochondrial apoptotic pathway or the extrinsic death receptor mediated pathways. In this review, we discuss the main apoptosis pathways and the key molecular targets which are the subject of several drug development approaches, the clinical development of these agents and the emerging resistance factors and combinatorial treatment approaches for this class of agents with existing and emerging novel targeted anti-cancer therapeutics.

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It's time to die: BH3 mimetics in solid tumors

Cited by 53 publications

References 125 publications

Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

Dengue Virus Dysregulates Master Transcription Factors and PI3K/AKT/mTOR Signaling Pathway in Megakaryocytes

Dual inhibition of anti-apoptotic proteins BCL-XL and MCL-1 enhances cytotoxicity of Nasopharyngeal carcinoma cells

Therapeutics Targeting the Core Apoptotic Machinery

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