Current overview on the clinical update of Bcl-2 anti-apoptotic inhibitors for cancer therapy

Suvarna, Vasanti; Singh, Vikas; Murahari, Manikanta

doi:10.1016/j.ejphar.2019.172655

Cited by 68 publications

(44 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…S 16A ). BAX is a well-known proapoptotic p53 target [ 54 ], constrained by antiapoptotic proteins such as BCL2L1 (BCL-XL) [ 55 ], and the BAX/BCL2L1 ratio was increased by TPT, and more-so the combo, all of which was p53-dependent (Fig. S 16A ).…”

Section: Resultsmentioning

confidence: 99%

Functional genomics identifies new synergistic therapies for retinoblastoma

et al. 2020

View full text Add to dashboard Cite

Local intravitreal or intra-arterial chemotherapy has improved therapeutic success for the pediatric cancer retinoblastoma (RB), but toxicity remains a major caveat. RB initiates primarily with RB1 loss or, rarely, MYCN amplification, but the critical downstream networks are incompletely understood. We set out to uncover perturbed molecular hubs, identify synergistic drug combinations to target these vulnerabilities, and expose and overcome drug resistance. We applied dynamic transcriptomic analysis to identify network hubs perturbed in RB versus normal fetal retina, and performed in vivo RNAi screens in RB1 null and RB1 wt ; MYCN amp orthotopic xenografts to pinpoint essential hubs. We employed in vitro and in vivo studies to validate hits, define mechanism, develop new therapeutic modalities, and understand drug resistance. We identified BRCA1 and RAD51 as essential for RB cell survival. Their oncogenic activity was independent of BRCA1 functions in centrosome, heterochromatin, or ROS regulation, and instead linked to DNA repair. RAD51 depletion or inhibition with the small molecule inhibitor, B02, killed RB cells in a Chk1/Chk2/p53-dependent manner. B02 further synergized with clinically relevant topotecan (TPT) to engage this pathway, activating p53–BAX mediated killing of RB but not human retinal progenitor cells. Paradoxically, a B02/TPT-resistant tumor exhibited more DNA damage than sensitive RB cells. Resistance reflected dominance of the p53–p21 axis, which mediated cell cycle arrest instead of death. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53–BAX axis, and synergized with B02, TPT or both to override resistance. These data expose new synergistic therapies to trigger p53-induced killing in diverse RB subtypes.

show abstract

Section: Resultsmentioning

confidence: 99%

Functional genomics identifies new synergistic therapies for retinoblastoma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Identification of the important role of BCL2 in cancer development and chemo resistance, rendered it as an ideal target for cancer therapeutics 1 , 7 . Development of the BCL2 inhibitor, ABT199 has shown that, targeting BCL2 specifically can be a precise choice to avoid dose limiting toxicity 13 , 14 . Importantly, several BCL2 inhibitors are currently under clinical trials 15 ( https://clinicaltrials.gov/ct2/results?cond=BCL2+inhibitors&term=&cntry=&state=&city=&dist =).…”

Section: Introductionmentioning

confidence: 99%

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Sharma

Varsha

Kumari

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Small molecule inhibitors targeting BCL2 are explored as anticancer therapeutics. Previously, we have reported identification and characterization of a novel BCL2 inhibitor, Disarib. Disarib induced cancer cell death in a BCL2 dependent manner in different cancer cell lines and mouse tumor models when it was administered intraperitoneally. In the present study, using two syngeneic mouse models, breast adenocarcinoma (EAC) and Dalton’s lymphoma (DLA), we show that oral administration of Disarib resulted in significant tumor regression in a concentration dependent manner. Importantly, tumor developed in both female and male mice were equally sensitive to Disarib. Further, we have investigated the toxicity of Disarib in normal cells. Single dose toxicity analysis of Disarib in male and female mice after oral administration revealed no significant variations compared to control group for parameters such as body weight, food and water consumption and behavioural changes which were analysed for the entire period of study. Haematological and histopathological analyses also did not show any significant difference from the control groups. Thus, our results reveal safe use of Disarib as a small molecule inhibitor and provide the foundation for investigation of other preclinical studies.

show abstract

“…This combination offers interesting perspectives for the clinical use of ABT-263 (Navitoclax, the orally available ABT-737 analog). Due to its ability to antagonize the survival function of Bcl-x L in platelets 61 , Navitoclax triggers thrombocytopenia, which is its major dose-limiting side-effect. As Naftopidil synergizes with ABT-737, it might allow a dose reduction of ABT-263, thereby alleviating this BH3-mimetic side-effect.…”

Section: Discussionmentioning

confidence: 99%

Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib

et al. 2020

View full text Add to dashboard Cite

Ovarian cancer represents the first cause of mortality from gynecologic malignancies due to frequent chemoresistance occurrence. Increasing the [BH3-only Bim, Puma, Noxa proapoptotic]/[Bcl-x L , Mcl-1 antiapoptotic] proteins ratio was proven to efficiently kill ovarian carcinoma cells and development of new molecules to imbalance Bcl-2 member equilibrium are strongly required. Drug repurposing constitutes an innovative approach to rapidly develop therapeutic strategies through exploitation of established drugs already approved for the treatment of noncancerous diseases. This strategy allowed a renewed interest for Naftopidil, an α 1-adrenergic receptor antagonist commercialized in Japan for benign prostatic hyperplasia. Naftopidil was reported to decrease the incidence of prostate cancer and its derivative was described to increase BH3-only protein expression in some cancer models. Based on these arguments, we evaluated the effects of Naftopidil on ovarian carcinoma and showed that Naftopidil reduced cell growth and increased the expression of the BH3-only proteins Bim, Puma and Noxa. This effect was independent of α 1-adrenergic receptors blocking and involved ATF4 or JNK pathway depending on cellular context. Finally, Naftopidil-induced BH3only members sensitized our models to ABT-737 and Trametinib treatments, in vitro as well as ex vivo, in patientderived organoid models.

show abstract

Current overview on the clinical update of Bcl-2 anti-apoptotic inhibitors for cancer therapy

Cited by 68 publications

References 92 publications

Functional genomics identifies new synergistic therapies for retinoblastoma

Functional genomics identifies new synergistic therapies for retinoblastoma

Acute toxicity analysis of Disarib, an inhibitor of BCL2

Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib

Contact Info

Product

Resources

About