Search Results (95)

Background: BH3 mimetics (such as venetoclax and navitoclax) are increasingly investigated in the context of the “one-two punch” anticancer strategy, wherein senescence-inducing therapies are combined with senolytic clearance. However, real-world pharmacovigilance evidence describing hematologic adverse event (AE) patterns and serious outcomes for venetoclax versus navitoclax in such combination settings remains limited. This study aims at providing an expectation based on the current reporting of the safety implications of senolytics combined with senescence-inducing therapy in clinical practice. Methods: We analyzed de-duplicated U.S. FDA Adverse Event Reporting System (FAERS) reports retrieved on 1 August 2025. Venetoclax reports (Q2 2016–Q2 2025) were categorized as monotherapy or combination with senescence-inducing chemotherapy (predefined based on published evidence of therapy-induced senescence [TIS]). Hematologic AEs were grouped into three categories (isolated low WBC, isolated low platelet count, and multi-lineage cytopenia). Disproportionality analyses were conducted using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) with 95% CIs and chi-squared testing. Navitoclax reports were analyzed descriptively due to limited volume. Results: A total of 47,508 venetoclax reports were included (34,485 monotherapy; 13,023 combination). Compared with monotherapy, combination therapy showed disproportionate reporting signals (ROR/PRR; reflecting reporting disproportionality rather than incidence or causal risk) for low WBC (ROR 2.87, PRR 2.59) and multi-lineage cytopenias (ROR 3.54, PRR 2.94), while isolated low platelet count was under-represented (ROR 0.31, PRR 0.32). For outcomes, combination therapy demonstrated higher reporting signals for life-threatening outcomes (ROR 7.06, PRR 6.56), hospitalization (ROR 1.74, PRR 1.39), and other outcomes (ROR 2.36, PRR 1.57), while death (ROR 0.55, PRR 0.65) and non-serious outcomes (ROR 0.26, PRR 0.29) were proportionally less reported (all p < 0.001). Navitoclax had 172 reports; hematologic cytopenias and serious outcomes were frequent, but analyses were descriptive only. Conclusions: In FAERS, venetoclax combined with senescence-inducing chemotherapy shows stronger reporting signals for leukopenia and multi-lineage cytopenias and for several serious outcome categories compared with monotherapy. These reporting patterns highlight the need for further care in terms of clinical implementation of the currently investigated senolytics prior to the consideration of the “one-two punch” strategy. Full article

Tumor necrosis factor alpha (TNF-α) serves as a major regulator of inflammatory responses. The initial, critical release and activation of TNF-α in acute pancreatitis (AP) is primarily triggered within the pancreatic acinar cells through intracellular mechanisms in response to initial injury. This local, acinar cell-derived TNF-α recruits immune cells into the pancreas, which then produce more TNF-α, leading to the amplification of the inflammatory cascade. This opinion emphasises the role of TNF-α-mediated dysfunction of pancreatic β-cells and apoptosis induction through the Bax/Bcl-2/caspase-3 pathway. AP is often diagnosed by autodigestive pancreatic damage and systemic inflammatory response with transient or persistent hyperglycaemia. TNF-α signalling takes place through TNFR1, which initiates apoptotic events that weaken mitochondrial integrity leading to β-cell disruption and diminished insulin secretion. Studies reported TNF-α-mediated increases in Bax expression, anti-apoptotic Bcl-2 suppression and activation of caspase-3. Therapeutic strategies such as TNFR1 inhibitors, Bax/Bcl-2 modulators and BH3 mimetics possess great potential to preserve β-cell integrity. However, TNF-α inhibition requires a careful approach in order to avoid compromising immune defence in AP patients. TNF-α-driven β-cell apoptosis represents a strong link between inflammation and metabolic dysfunction that makes it a suitable target for AP. Future directions should prioritise translational research in human cohorts and developing receptor-specific interventions to balance immune modulation with β-cell preservation. Full article

The BCL-2 family of proteins plays a central role in the regulation of apoptosis, with BCL-2 and BCL-xL representing two of its most prominent antiapoptotic members. This review explores the molecular regulation of BCL-2 and BCL-xL genes, emphasizing the structural domains that define the functions of the broader BCL-2 family. Beyond their canonical roles in preventing mitochondrial outer membrane permeabilization, both proteins contribute significantly to cancer development. Their overexpression enhances invasiveness and tumor progression, supports angiogenesis, and critically modulates cellular responses to chemotherapy, often conferring drug resistance. Additional non-apoptotic functions, including roles in metabolism, mitochondrial dynamics, and cellular homeostasis, further expand their biological relevance. Clinical trials exploring strategies to inhibit BCL-2 and BCL-xL, including selective BH3 mimetics and combination regimens, are discussed with emphasis on their potential and limitations in oncology. Overall, this review highlights the multifaceted contributions of BCL-2 and BCL-xL to cancer biology and underscores the importance of continued efforts to refine targeted therapeutic approaches. Full article

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt locking. We also examine strategies to overcome resistance, including combination therapies and immunomodulatory approaches. Beyond oncology, we highlight the expanding therapeutic potential of BH3 mimetics in autoimmune, fibrotic, and infectious diseases, as well as regenerative and anti-aging medicine. Finally, we discuss predictive biomarkers and tissue-specific responses that inform precision therapy. Together, these insights underscore the promise of BH3 mimetics and the need for continued multidisciplinary research to optimize their clinical impact. Full article

Since its discovery, the BTK inhibitor ibrutinib has redefined the standard treatments for hematological cancers, such as chronic lymphocytic leukemia (CLL). However, concerns exist regarding its secondary effects in humans and its occasional lack of efficacy in certain malignancies. Therefore, combined therapies with ibrutinib have emerged as promising new approaches. In this study, we aimed to explore its therapeutic potential through different approaches. For this purpose, we combined this drug with the BH3 mimetics ABT-199 and ABT-737, which inhibit anti-apoptotic members of the Bcl-2 family, and with the PDK1 inhibitor dichloroacetate (DCA), respectively. As cell models, we used ex vivo samples from patients and also selected the in vitro CLL cell line Mec-1, generating two sub-lines overexpressing Bcl-XL and Mcl-1, a common feature in this cancer. Results demonstrated a synergistic effect for both approaches, in all tumor cells tested, for both cytostatic and cytotoxic effects. Mechanistically, the expression of Bcl-2-family proteins was explored, exhibiting increases in pro-apoptotic, but also in anti-apoptotic, proteins upon ibrutinib treatment and a relative increase in the amount of the pro-apoptotic protein PUMA after treatment with DCA. Our data provides new insights into combined therapies with ibrutinib for CLL, which further expands our knowledge and the potential of this drug for cancer treatment. Full article

The MIM1-BH3 mimetic, which inhibits the Mcl-1 antiapoptotic protein, may be an efficacious molecule able to induce apoptosis. Previously, we found that moxifloxacin (MXFL) is able to modulate Mcl-1 protein expression. Therefore, in the current study, we assessed the impact of the MXFL, MIM1, and MXFL/MIM1 mixtures on viability and apoptosis in amelanotic A375 and melanotic G361 melanoma cells. The obtained results showed that MXFL and MIM1 exerted high cytotoxic and proapoptotic potential. In the case of two-component models, we have demonstrated that the use of the MIM1 and MXFL mixtures resulted in a significant intensification of both cytotoxic and proapoptotic activity, shown as a modulatory effect on the early and late phases of apoptosis toward the analyzed melanoma cells when compared with MIM1 or MXFL alone. We report, for the first time, the high proapoptotic activity of MIM1 and MXFL applied in a two-component model toward melanoma cells, pointing to the Mcl-1 protein as an important molecular target. The observed potential synergistic mode of action—expressed as cytotoxic and proapoptotic activity enhancement, detected for MIM1 and MXFL—may represent a new direction for further in vitro and in vivo experiments concerning the role of the Mcl-1 protein in the treatment of melanoma. Moreover, the presented results certainly contribute to expanding the knowledge of the pharmacology of both fluoroquinolones and BH3 mimetics, and also enable a better understanding of melanoma cell biology. Full article

Cellular senescence is a state of the durable cell cycle arrest of dysfunctional cells, which has been associated with the promotion of tumor cell reprogramming into a stem cell state. We previously reported that the mixed lineage kinase (MLK) inhibitor CEP-1347 promotes the differentiation of glioma stem cells (GSCs)—key contributors to glioblastoma recurrence and therapy resistance—into non-stem tumor cells. However, we also noted that CEP-1347–treated GSCs exhibited a morphological change suggestive of senescence. Therefore, we herein investigated whether CEP-1347 induces senescence in GSCs and, consequently, if senescent GSCs may be eliminated using senolytics. Cell death induced by CEP-1347 in combination with senolytic agents or with the knockdown of anti-apoptotic BCL2 family genes, as well as the effects of CEP-1347 on the expression of senescence markers and anti-apoptotic Bcl-2 family proteins, were examined. The results obtained showed that CEP-1347 induced senescence in GSCs accompanied by the increased expression of Bcl-xL. Among the panel of senolytic agents tested, navitoclax, a BH3 mimetic, efficiently induced cell death in GSCs when combined with CEP-1347 at concentrations clinically achievable in the brain. The knockdown of Bcl-xL resulted in more pronounced GSC death in combination with CEP-1347 than that of Bcl-2. These results suggest that combining CEP-1347 with the targeting of Bcl-xL, the expression of which increases with CEP-1347-induced senescence, is a rational approach to ensure the elimination of GSCs, thereby improving the outcomes of glioblastoma treatment. Full article

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with poor prognosis, largely due to its high metastatic potential and resistance to conventional therapies. Recent advances in cancer biology have underscored the significance of regulated cell death pathways, including apoptosis, autophagic cell death (ACD), necroptosis, pyroptosis, and ferroptosis, in modulating tumor progression and therapeutic responses. This review provides the current insights into the molecular mechanisms underlying these cell death pathways and explores their therapeutic relevance in OSCC. Restoration of apoptosis using BH3 mimetics, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor agonists, and p53 reactivators shows promise for sensitizing OSCC cells to treatment. Autophagy plays context-dependent roles in cancer, acting as a tumor suppressor during early carcinogenesis by maintaining cellular homeostasis, and as a tumor promoter in established tumors by supporting cancer cell survival under stress. Targeting necroptosis and pyroptosis has emerged as a novel strategy for inducing cancer cell death, with compounds such as acetylshikonin and okanin demonstrating antitumor effects. Additionally, the induction of ferroptosis via lipid peroxidation and glutathione peroxidase 4 (GPX4) inhibition offers a promising avenue for overcoming drug resistance, with agents such as quercetin and trifluoperazine exhibiting preclinical success. Integration of these therapeutic approaches may enhance the OSCC treatment efficacy, reduce chemoresistance, and provide novel prognostic biomarkers for clinical management. Future studies should focus on optimizing combinatorial strategies that effectively leverage these pathways to improve OSCC patient outcomes. Full article

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/Bak^DKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. Full article

One of the hallmarks of cancer cells is their failure to respond to the cellular mechanism of apoptosis. The B-cell lymphoma 2 (BCL-2) family of proteins regulate apoptosis. Their ability to do so can be measured using several methods that in turn anticipate the fate of the cancer cell in response to apoptosis-inducing treatment. These assays ultimately identify the readiness of the cancer cell to undergo apoptosis, which is referred to as the mitochondrial priming state. These metrics, however, have been challenging to implement in the clinic. Methods: Here, we describe a unique method that relies on a panel of novel conformation-specific antibodies (termed PRIMAB) that can directly measure the mitochondrial priming state. These reagents are highly specific for complexes of their corresponding pro-survival protein interactions with the pro-apoptotic protein BIM. These BIM-containing heterodimeric complexes have long been established as hallmarks of primed cancer cells. Results: Using clinically amenable assay formats, PRIMABs were shown to detect the presence of these anti-apoptotic–pro-apoptotic complexes and their disruption by BH3-mimetic drugs. Moreover, PRIMABs were able to detect a shift in priming status following BH3-mimetic treatment, a factor associated with resistance to these drugs. In a panel of AML patient samples, we report a wide range of priming levels for each PRIMAB complex, demonstrating the potential for heterogeneity in responses. We also show that PRIMABs could be predictive of outcomes for AML patients following cytarabine-based treatment. Conclusions: PRIMABs provide novel and useful tools for cancer research and for clinical implementation as reagents providing predictive tests for treatment response. Full article

Acute myeloid leukemia (AML) has traditionally been linked to a poor prognosis, particularly in older patients who are ineligible for intensive chemotherapy. The advent of Venetoclax, a powerful oral BH3 mimetic targeting anti-apoptotic protein BCL2, has significantly advanced AML treatment. Its combination with the hypomethylating agent azacitidine (AZA/VEN) has become a standard treatment for this group of AML patients, demonstrating a 65% overall response rate and a median overall survival of 14.7 months, compared to 22% and 8 months with azacitidine monotherapy, respectively. However, resistance and relapses remain common, representing a significant clinical challenge. Recent studies have identified molecular alterations, such as mutations in FLT3-ITD, NRAS/KRAS, TP53, and BAX, as major drivers of resistance. Additionally, other factors, including metabolic changes, anti-apoptotic protein expression, and monocytic or erythroid/megakaryocytic differentiation status, contribute to treatment failure. Clinical trials are exploring strategies to overcome venetoclax resistance, including doublet or triplet therapies targeting IDH and FLT3 mutations; novel epigenetic approaches; menin, XPO1, and MDM2 inhibitors; along with immunotherapies like monoclonal antibodies and antibody–drug conjugates. A deeper understanding of the molecular mechanisms of resistance through single-cell analysis will be crucial for developing future therapeutic strategies. Full article

Background: Acute myeloid leukemia (AML) is a common and aggressive form of leukemia, yet current treatment strategies remain insufficient. Venetoclax, a BH3-mimetic approved for AML treatment, induces Bcl-2-dependent apoptosis, though its therapeutic efficacy is still limited. Therefore, new strategies to enhance the effect of venetoclax are highly sought. Valproic acid (VPA), commonly used for epilepsy, has also been studied for potential applications in AML treatment. Methods: AML cells were treated with venetoclax, with or without VPA. Cell viability was assessed using the trypan blue dye exclusion assay, while cell cycle progression was analyzed by flow cytometry. The expression of pro-apoptotic proteins Bax and Bak was measured by RT-qPCR. Results: Venetoclax and VPA individually had only mild effects on AML cell proliferation. However, their combination significantly inhibited cell growth and triggered pronounced cell death. This combination also led to the cleavage of poly (ADP-ribose) polymerase (PARP), a substrate of caspases, indicating activation of apoptosis. VPA treatment upregulated the expression of Bax and Bak, further supporting apoptosis induction. The cell death induced by the venetoclax–VPA combination was predominantly apoptotic, as confirmed by the near-complete blockade of cell death by a pan-caspase inhibitor. Conclusions: Our study demonstrates that VPA enhances venetoclax-induced apoptosis in AML cell lines, providing a novel role for VPA and suggesting a promising combinatory strategy for AML treatment. These findings offer valuable insights into potential clinical applications of venetoclax and VPA in AML management. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed to T-cell lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% of adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis and therapy resistance. Notch inhibition is a promising therapeutic target for personalized medicine, and a variety of strategies to prevent Notch activation, including γ-secretase (GS) inhibitors (GSIs) and antibodies neutralizing Notch receptors or ligands, have been developed. Disruption of apoptosis is pivotal in cancer development and progression. Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use. Full article

B-cell lymphoma 2 protein (Bcl-2) is an important regulator of cell apoptosis. Inhibitors that mirror the structural domain 3 (BH3) of Bcl-2 can activate apoptosis in cancer cells, making them a promising target for anticancer treatment. Hence, the present study aimed to investigate potential BH3-mimetic peptides from two vicilin-derived legume proteins from soybean and cowpea bean. The proteins were isolated and sequentially hydrolyzed with pepsin/pancreatin. Peptides < 3 kDa from vicilin-derived proteins from soybean and cowpea beans experimentally inhibited the growth of cultivated breast and prostate cancer cells. In silico analysis allowed the identification of six potential candidates, all predicted to be able to interact with the BH3 domain. The VIPAAY peptide from the soybean β-conglycinin β subunit showed the highest potential to interact with Bcl-2, comparable to Venetoclax, a well-known anticancer drug. Further experiments are needed to confirm this study’s findings. Full article

Acute leukemia is a group of aggressive hematological malignancies, with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) being the most common types. The biology of acute leukemia involves complex genetic and epigenetic alterations that lead to uncontrolled cell proliferation and resistance to apoptosis. Mitochondrial dysfunction is a feature of acute leukemia that results in altered energy production, unregulated cell death pathways, and increased cancer cell survival. Apoptosis, particularly via the mitochondrial pathway, is crucial for cellular homeostasis and cancer prevention. In acute leukemia, disruption of apoptosis is pivotal in disease development and progression, with elevated levels of anti-apoptotic proteins conferring a survival advantage to leukemia cells and promoting resistance to conventional therapies. Targeting mitochondrial apoptosis using BH3 mimetics and anti-apoptotic protein inhibitors is a viable therapeutic strategy. Alterations in the mitochondrial membrane potential, metabolism, and dynamics also contribute to the pathogenesis of acute leukemia. Continued research is vital for developing novel therapies and enhancing survival outcomes in patients with acute leukemia while minimizing the long-term adverse effects of treatment. In this narrative review, we provide a birds-eye view of the available scientific literature on the importance of mitochondria in acute leukemia, and discuss the role of BH3 mimetics in targeting the mitochondrial internal apoptotic machinery. Full article