You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic. For video creation, please contact our Academic Video Service.
Version Summary Created by Modification Content Size Created at Operation
1
Roberto Palacios-Ramirez
 -- 3445 2023-04-14 16:31:13 |
2 format
Jason Zhu
 Meta information modification 3445 2023-04-17 08:34:58 |

Video Upload Options

We provide professional Academic Video Service to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Barriuso, D.; Alvarez-Frutos, L.; Gonzalez-Gutierrez, L.; Motiño, O.; Kroemer, G.; Palacios-Ramirez, R.; Senovilla, L. Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence. Encyclopedia. Available online: https://encyclopedia.pub/entry/43070 (accessed on 18 July 2025).
Barriuso D, Alvarez-Frutos L, Gonzalez-Gutierrez L, Motiño O, Kroemer G, Palacios-Ramirez R, et al. Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence. Encyclopedia. Available at: https://encyclopedia.pub/entry/43070. Accessed July 18, 2025.
Barriuso, Daniel, Lucia Alvarez-Frutos, Lucia Gonzalez-Gutierrez, Omar Motiño, Guido Kroemer, Roberto Palacios-Ramirez, Laura Senovilla. "Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence" Encyclopedia, https://encyclopedia.pub/entry/43070 (accessed July 18, 2025).
Barriuso, D., Alvarez-Frutos, L., Gonzalez-Gutierrez, L., Motiño, O., Kroemer, G., Palacios-Ramirez, R., & Senovilla, L. (2023, April 14). Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence. In Encyclopedia. https://encyclopedia.pub/entry/43070
Barriuso, Daniel, et al. "Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence." Encyclopedia. Web. 14 April, 2023.
Involvement of Bcl-2 Family Proteins in Tetraploidization-Related Senescence
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24076374

The B-cell lymphoma 2 (Bcl-2) family of proteins is the main regulator of apoptosis. However, multiple emerging evidence has revealed that Bcl-2 family proteins are also involved in cellular senescence. On the one hand, the different expression of these proteins determines the entry into senescence. On the other hand, entry into senescence modulates the expression of these proteins, generally conferring resistance to apoptosis. With some exceptions, senescent cells are characterized by the upregulation of antiapoptotic proteins and downregulation of proapoptotic proteins. Under physiological conditions, freshly formed tetraploid cells die by apoptosis due to the tetraploidy checkpoint. However, suppression of Bcl-2 associated x protein (Bax), as well as overexpression of Bcl-2, favors the appearance and survival of tetraploid cells.

Bcl-2 family proteins senescence apoptosis

1. Introduction

Members of the B-cell lymphoma 2 (Bcl-2) family proteins are known to be the main regulators of the intrinsic apoptosis pathway. Antiapoptotic proteins prevent the triggering of apoptosis, whereas proapoptotic proteins favor the induction of programmed cell death. Therefore, the presence or absence of these proteins is determinant in the survival and resistance of cells to an apoptotic signal. However, Bcl-2 family proteins also exert other noncanonical functions affecting cellular senescence, bioenergetic metabolism and redox homeostasis [1].
Tetraploidy is considered a precancerous stage. In 2010, Davoli et al. proposed that, at the onset of tumorigenesis, cells may undergo permanent telomere dysfunction accompanied by DNA damage that would result in permanent cell cycle arrest. Cells that manage to escape this arrest, due to the absence of p53, would undergo endoreplication, giving rise to tetraploid cells [2]. Additionally, chemotherapeutic drugs include antimitotic agents such as taxanes and vinca alkaloids, which mechanism of action is based on tubulin binding. The prolonged use of antimitotic agents can cause chronic arrest in mitosis, cell death or mitotic slippage, leading to tetraploidy, apoptosis and/or senescence [3][4][5]. These chemically induced tetraploid cells, with functional p53, arrest their cell cycle G1, known as “tetraploidy arrest”, and undergo senescence [6]. Antimitotic agents are used in anticancer chemotherapy and can induce the tetraploidization of malignant cells in vivo [7] and promote therapy-induced senescence (TIS). Senescent cells originating from TIS can generate tumor resistance or lead to cancer recurrence if the stability of the proliferative arrest is weakened [8]. Targeting these senescent cells before they escape from proliferative arrest is key to improving the success of cancer therapies.

2. Role of the Bcl-2 Family in Senescence

2.1. Antiapoptotic Bcl-2 Proteins

Accumulated evidence has demonstrated that antiapoptotic Bcl-2 proteins are critical for senescence establishment [1]. While high levels of Bcl-2 and Bcl-w can trigger senescence in response to several stimuli, such as DNA damage or hypoxia, high levels of Bcl-xL and Mcl-1 may prevent the cells from entering into oncogene-induced senescence (OIS) and TIS. Senescent cells, however, present high levels of Bcl-2, Bcl-xL and Mcl-1 that halt the ability of the cells to follow a programmed cell death. For instance, expression levels of Bcl-w, Bcl-xL and Bcl-2 are increased in DNA damage-induced senescence by etoposide and ionizing irradiation [9], which are known to increase the presence of tetraploid cells [10][11]. In turn, subsequent studies have shown that the presence of Bcl-2, Bcl-w and Bcl-xL underlies the resistance of senescent cells to apoptosis [9][12]. In both cancer and senescence, overexpression of Bcl-2 counteracts the proapoptotic genes Puma and Noxa, thereby limiting apoptosis [13]. However, Baar et al. showed reduced Bcl-2 but upregulated Puma and Bim in genomically stable primary human lung myofibroblasts IMR90 induced to undergo senescence by ionizing radiation, suggesting that IMR90 senescent cells are destined for death by apoptosis, but somehow, the execution of the death program is impaired.
Entry into, and the maintenance of cells in, senescence depends on the upregulation of Bcl-2, meaning that senescence is associated with elevated levels of Bcl-2 [9][14]. Moreover, the overexpression of Bcl-2 potentiates senescence cancer cells, such as in K562 leukemia cells [15]. Therefore, Bcl-2, which can inhibit both apoptosis triggering and proliferation, causes a senescence-like phenotype [16]. The overexpression of Bcl-2 correlates with cell cycle arrest, which could promote senescence [17]. In fact, cell cycle arrest in G1 is mediated not only by the overexpression of Bcl-2 but also by the inhibition of cyclin-dependent kinase (Cdk)2 activity and induction of p27Kip1 [18]. Indeed, the overexpression of Bcl-2 upregulates the levels of p27 Kip1 and the nucleolar phosphoprotein p130, a member of the pRb pocket protein family, which forms repressive complexes with the transcription factor E2F4, inhibiting its release and thus preventing cell cycle progression in quiescent fibroblasts [19]. Several types of stimuli require the presence of Bcl-2 to induce senescence, such as (1) DNA damage and serum starvation, through p38MAPK, in OI [20]; (2) hypoxia-induced senescence, independent of p53 and p16INK4a [21]; and (3) chemotherapy-induced cell growth inhibition that involves the accumulation of p53/p16INK4a and senescence markers [22]. Lee et al. first described in 2010 how inhibition of the c-Jun N-terminal kinase (JNK), a regulator of oxidative DNA damage, by SP600125 induces premature senescence. The inhibition of JNK results in the dephosphorylation of Bcl-2, followed by the accumulation of ROS. The increased production of ROS induces the DNA damage response (DDR), leading to cell cycle arrest. The inhibition of cell cycle progression induced by SP600125 treatment is characterized by the upregulation of p53 and p21Waf1/Cip1 and downregulation of pRb, as well as an increase in the inactive phospho-cell division control 25C (P-Cdc25C) phosphatase and a decrease in the cyclin B and Cdk2 levels [23]. Of note, SP600125 induces G2/M cycle arrest and an increase in aneuploid cells [24][25]. Conversely to Bcl-2 or Bcl-xL, little is known about the role of Bcl-w in senescence. However, it is known that Bcl-w overexpression enhances cellular senescence by activating the p53/neurogenic locus notch homolog protein 2 (Notch2)/p21Waf1/Cip1 axis [26].
Interestingly, Bcl-xL has a dual effect on senescence. The natural upregulation of Bcl-xL during megakaryocyte differentiation or genetically overexpressed Bcl-xL in MEFs and in primary cultures of human lymphocytes reduce entry into senescence [27]. However, it has been shown that several cancer senescent cell types, such as triple-negative breast cancer cell lines and pilocytic astrocytoma tumor cells, exhibit high levels of the Bcl-xL protein [27][28], as well as in both pancreatic intraepithelial neoplasia (PanIn) and pancreatic ductal adenocarcinoma (PDAC) [29]. The presence, or induced upregulation, of Bcl-xL reduces entry into senescence stimulated by various stimuli. For instance, (1) the overexpression of Bcl-xL suppresses OIS in low-grade PanIn and apoptosis in high-grade PanIn [29]; (2) Bcl-xL blocks p38MAPK activation and inhibits senescence induction by preventing p53-induced ROS generation [30]; (3) the induction of DNA damage causes cell cycle arrest at the G2/M checkpoint, as well as translocation of Bcl-xL to the nucleus occurs, where it binds to Cdk1, inhibiting its kinase activity and stabilizing the senescence program [31]; (4) treatment with the topoisomerase I inhibitor SN38 induces and maintains stable p53- and p21Waf1/Cip1-dependent growth arrest due to increased Bcl-xL expression [32]; and (5) CCC-021-TPP, the novel pyrrole–imidazole polyamide targeting a specific mutation in mitochondrial DNA, causes cellular senescence accompanied by significant induction of the antiapoptotic Bcl-xL [33]. Noteworthy, an increased Bcl-xL expression contributes to the protection against apoptosis in the human colon cancer cell line HCT116 [32]. In turn, the ablation of Bcl-xL decreased the survival of radiated glioblastoma multiforme (GBM) cells [34], as well as induced OIS and apoptosis in PDAC [29]. Moreover, permanent cell cycle arrest in response to OIS generally occurs through the combined activation of the p53/p21Waf1/Cip1 and p16INK4a-pRb pathways. Malignant cells having escaped OIS rely on survival pathways induced by Bcl-xL/Mcl-1 signaling [35]. Therefore, not only the overexpression of Bcl-xL represses the entry into senescence but senescent cells also show elevated levels of Bcl-xL preventing apoptosis [27].
As Bcl-xL, Mcl-1 acts as a senescence inhibitor, since the overexpression of Mcl-1 in tumor cells is crucial for blocking the induction of senescence [36]. Recently, Troiani et al. showed that senescent tumor cells depend on Mcl-1 for their survival. Interestingly, Mcl-1 is upregulated in senescent tumor cells, including those expressing low levels of Bcl-2 [37]. In a mechanism such as that described for Bcl-xL, treatment with G2/M blocking agents increases the interaction between a shortened form of the Mcl-1 polypeptide, mainly located in the nucleus, with Cdk1, reducing its kinase activity and inhibiting cell growth [38]. During extended mitotic arrest, Mcl-1 has been identified as a critical factor to determine whether cells trigger apoptosis or mitotic slippage [39]. The overexpression of Mcl-1 inhibits TIS and promotes tumor growth, whereas the downregulation of Mcl-1 delays tumor growth in vivo [36]. The anti-TIS function of Mcl-1 can be inhibited by a loop domain mimetic peptide [40]. Mcl-1-regulated TIS depends on the generation of ROS—more specifically, mitochondrial ROS—and subsequent activation of the DNA damage response. Mcl-1 prevents the expression of NADPH oxidase 4, limiting its availability in mitochondria and thus decreasing mitochondrial ROS production during TIS [41].

2.2. Multidomain Proapoptotic Bcl-2 Proteins

Aging is associated with the balance between Bax and Bcl-2 expression. However, this balance seems to be different, depending on the cell type or the organism. In mice prone to accelerated senescence (SAMP8 mice), decreased Bcl-2 expression and increased Bax expression are observed [42]. In turn, senescent human diploid fibroblasts show high levels of Bcl-2 and low expression of Bax, which is associated with resistance to oxidative stress-induced apoptosis [43]. Thus, Bax is the most studied multidomain proapoptotic protein in senescence. Bax upregulation has been observed under different circumstances in DNA damage-induced senescence. For instance, the knockdown of Cdk2-associated protein-1 (Cdk2ap1) increases the percentage of cells exhibiting DNA damage characterized by γ-H2AX, as well as increased p53/p21Waf1/Cip1 and Bax, which reduces proliferation and induces premature senescence in primary human dermal fibroblasts [44]. The combined treatment of AMG 232, a potent small molecule inhibitor that blocks the interaction of mouse double minute 2 homolog (Mdm2) and p53, and radiation results in the accumulation of γ-H2AX-related DNA damage, a significant increase in Bax expression and induction of senescence in human tumors [45]. The treatment of human breast cancer MCF-7 cells with metformin or phenformin induces increases in p53 protein levels and p21Waf1/Cip1 and Bax transcription in a dose-dependent manner, leading to senescence [46]. Pancreatic cancer is associated with the elevated expression of cyclin B1 and Mdm2, as well as lower expression of Bax and p21Waf1/Cip1. However, the silencing of cyclin B1 decreases proliferation and the proportion of cells in the S phase while increasing apoptosis, senescence and the proportion of cells in the G0/G1 phase. This increase in senescence was accompanied by enhanced levels of p21Waf1/Cip1 and Bax [47]. Overexpression of the inhibitor of growth protein 5 (Ing5) causes (1) the suppression of proliferation and induction of G2/M arrest, (2) apoptosis, (3) senescence and (4) chemoresistance to cisplatin and paclitaxel in human primary GB cell line U87. At the molecular level, overexpression of Ing5 in the U87 line results in a lower expression of Cdc2 and Cdk4 but higher expression of p21Waf1/Cip1, p53 and Bax [48].

2.3. BH3-Only Proapoptotic Bcl-2 Proteins

In general, the involvement of proapoptotic BH3-only proteins is unclear and may even be controversial in senescence. As described below, depending on the circumstances, the expression of these proteins may be increased or reduced depending on the context. Therefore, the implication of these proteins in senescence does not seem to be decisive and could be merely an accessory role.
MEFs expressing p53R1752P, a hypomorphic mutation that favors senescence versus apoptosis in response to UVB, fail to upregulate Puma and Noxa to induce apoptosis but can enter senescence by the upregulation of p21Waf1/Cip1 [13]. However, the upregulation of Puma has been observed in senescent IMR90 cells [49] and on entry into senescence after Cdk2ap1 knockdown [44]. Bim shows low expression in aged peripheral naive CD4 T cells exhibiting higher levels of p16INK4a and p19ARF [50], as well as in senescence in K562 cells [15]. Additionally, Bim expression is reduced in spindle mitotic stress induced by deletion of the transforming centrosomal acidic coiled-coil protein (TACC)3, which links microtubule integrity to spindle poison-induced cell death, G1 cell arrest and the upregulation of nuclear p21Waf1/Cip1 [51]. However, the upregulation of Bim has been observed in senescent IMR90 cells [49], as well as after the treatment of uveal melanoma with a combination of mitogen-activated protein kinase kinase inhibitors (MEKi) with a DNA methyltransferase inhibitor (DNMTi) that induces an increase in p21Waf1/Cip1 expression [52]. The relative Bad levels were elevated from 60% to 130% in prolonged senescent cultures of porcine pulmonary artery endothelial cells (PAECs), whereas the steady-state Bcl-2 levels decreased to less than 20% favoring cell death [53]. On the other hand, Bad influences carcinogenesis and cancer chemoresistance. When unphosphorylated, Bad dimerizes with Bcl-xL and Bcl-2, releasing Bax and allowing the ignition of apoptosis. However, when phosphorylated, Bad (pBad) is unable to heterodimerize with Bcl-2 or Bcl-xL, and therefore, Bax is not released to initiate apoptosis. Higher levels of pBad have been observed in normal immortalized cells compared with tumor cells [54]. Bmf is a functional target of miR-34c-5p, and long noncoding RNA (lncRNA)-ES3 acts as a competing endogenous RNA (ceRNA) of miR-34c-5p to regulate the expression of Bmf in human aorta VSMCs. Thus, the lncRNA-ES3/miR-34c-5p/Bmf axis upregulates calcification/senescence of vascular smooth muscle cells (VSMCs) [55]. Bnip3 is activated in hypoxic human papillomavirus type 16 (HPV16)-positive cervical cancer cells, allowing the evasion of senescence [56]. Overexpressing Bnip3 fibroblasts show the key features of a senescence phenotype, such as the induction of p21Waf1/Cip1 and p16Ink4a, cell hypertrophy and the upregulation of β-galactosidase activity [57]. Urolithin A attenuates auditory cell senescence by activating mitophagy. However, the ablation of Bnip3, which acts as a mitophagy-related gene, results in the abrogation of UA-induced anti-senescent activity [58].

3. The Bcl-2 Family Proteins as a Target for Senolytic Agents

TIS has been identified after radiation or genotoxic chemotherapy. Arrest can occur in both G1 and G2/M and is characterized by an increased expression of p16Ink4a, p21Waf1/Cip1 and p27Kip1. TIS may function as an alternative onco-suppressive mechanism when apoptotic pathways are disabled. Moreover, TIS can induce persistent cell cycle arrest at any stage of tumor development [59]. However, the data obtained in recent years show the danger of senescent cancer cells, since (1) senescent cells can escape growth arrest and resume cell proliferation, (2) senescent cancer cells that manage to escape arrest exhibit stem cell-like characteristics and (3) senescent tumor cells may escape recognition and elimination by the immune system [60].
Senolytics are senotherapeutics that selectively eliminate senescent cells [61][62][63]. Inhibitors of the Bcl-2 family have been identified among the different types of compounds with senolytic activity [64]. ABT-199 (Venetoclax) targets only the Bcl-2 protein [65]. ABT-263 (also known as Navitoclax) is an orally bioavailable Bad-like BH3 mimetic. ABT-263 maintains a high affinity for Bcl-2, Bcl-w and, especially, Bcl-xL. Reportedly, ABT-263 inhibits the interaction of Bcl-2 and Bcl-xL, leading to the release of Bim, as well as to trigger the translocation of Bax, initiating the intrinsic pathway of apoptosis [66]. The addition of senolytic agents such as ABT-199 or ABT-263 after irradiation induces apoptotic cell death in soft tissue sarcomas (STS), which undergo TIS with increased levels of the antiapoptotic Bcl-2 family [67]. The combination of gemcitabine with everolimus or ionizing radiation induces the senescence of malignant meningioma cells, which are eliminated with ABT-263 [68][69]. Wogonin, a well-known natural flavonoid compound, induces cellular senescence in T-cell malignancies and activates DDR mediated by p53, as well as the upregulated expression of Bcl-2 in senescent T cells. ABT-263 induces apoptotic cell death in wogonin-induced senescent cells [70]. In 2020, Muenchow et al. proposed a combinatorial treatment of A-199 and the proteosome inhibitor bortezomib (BZB) against STS, resulting in a sensitization to apoptosis by the simultaneous release of proapoptotic proteins such as Bax, Bok and Noxa and inhibition of Mcl-1 [71]. ABT-263 is an effective senolytic in senescent human umbilical vein epithelial cells (HUVECs) and IMR90 cells [72], irradiated or old normal murine senescent bone marrow hematopoietic stem cells and senescent muscle stem cells [73] and prostate cancer TIS [8]. The sequential combination of TIS and ABT-263 redirects the response towards apoptosis by interfering with the interaction between Bcl-xL and Bax [74]. Breast cancer Tp53+/+ cells depend on Bcl-xL to survive TIS. These cells can be killed using ABT-263, although sensitivity takes days to develop. However, a low expression of Noxa confers resistance to ABT-263 in some cells, requiring the additional inhibition of Mcl-1 [75].
ABT-737, a small molecule cell-permeable Bcl-2 antagonist that acts as a BH3 mimetic, inhibits Bcl-2, Bcl-w and Bcl-xL proteins, causing the preferential apoptosis of senescent cells induced by DNA damage [9][49]. Although the mechanism of action of ABT-737 has not been described in detail, it is known that ABT-737 inhibits the protective effect of Bcl-2 and Bcl-xL, an effect that is dependent on Bax or Bak, and activates the cleavage of caspases 8/9 in multiple myeloma cells [76]. ABT-737 eliminates Cox2-expressing senescent cells from PanIn lesions [77], and both ABT-737 and Navitoclax have shown a senolytic effect on senescent glioblastoma cells induced by the DNA-methylating drug temozolomide (TMZ) [78].
A1331852, a small molecule BH3 mimetic, inhibits Bcl-xL. Radiation plus TMZ is a common treatment in GBM that induces a state of senescence and sustained proliferative arrest. The use of Bcl-xL inhibitors (A1331852, A1155463 and A-263) increases the vulnerability of GBM to TMZ treatment [34]. However, the use of ABT-199 plus TMZ has shown contradictory effects in GBM [34][79]. Since Bcl-xL has been observed to be upregulated in senescent cholangiocytes induced by ionizing radiation, A1331852 reduces its presence by 80% [80], whereas Bak plays a key role in A-1331852-induced apoptosis in senescent chondrocytes [81]. The treatment of Dox combined with A-1331852 in different subcutaneous xenograft models of solid tumors shows the disruption of Bcl-xL:Bim complexes and induces cytochrome c release, activation of caspases 3/7 and externalization of phosphatidylserine, features of apoptosis [82][83]. A-1331852 upregulates the expression of Bid and Bax. In fact, A-1331852 promotes the apoptosis of senescent human lung A549 cells by influencing the interaction between Bcl-xL and Bid and that between Bcl-xL and Bax [84]. Both A1331852 and A1155463 are senolytic for ionizing radiation-induced senescent HUVECs and IMR90 cells. Treatment with A1155463 after ionizing irradiation also induces the cleavage of caspase 3/7 [85].
Other types of Bcl-2 family inhibitors that act as senolytic agents are small molecule Mcl-1 inhibitors such as A1210477 and S63845. A1210477 synergizes with EE-84, an aplysinopsin that induces a senescent phenotype in K562 cells [86]. Recently, it has been described that treatment with the Mcl-1 inhibitor S63845 leads to the complete elimination of senescent tumor cells and metastases [37]. The treatment of myeloma with A1210477 has been shown to disrupt Mcl-1/Bak complexes, and Bak release would promote cell death. However, free Bak can be recaptured by Bcl-xL, leading to a resistance to A1210477 [87]. Similarly, S63845-induced apoptosis occurs in a Bak-dependent manner in solid tumor-derived cell lines [88]. S64315 enhances the selective senolytic effect of ABT-263 and ABT-737. Radiation-induced retinal pigment epithelium senescent cells that survive treatment with the selective Mcl-1 inhibitor have been found to express increased levels of the Bcl-xL protein [64]. The combination of inhibitors of antiapoptotic proteins of the Bcl-2 family with taxanes and vinca alkaloids increases the efficacy of microtubule inhibitors, which would make it possible to reduce the doses of these chemotherapeutic agents while reducing their toxicity [39].
According to Wei et al., the antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1 are bound to the multidomain proapoptotic proteins Bax and Bak, inhibiting their activation. Following a cellular stress stimulus, the expression of proapoptotic BH3-only proteins Bad and Noxa is increased. Bad binds preferentially to Bcl-2 and Bcl-xL, whereas Noxa binds preferentially to Mcl-1. In consequence, Bad and Noxa free Bax and Bak from binding to antiapoptotic proteins and activating them, thus initiating the apoptotic pathway [89]. Since antiapoptotic Bcl-2 family proteins are upregulated in irradiation-induced senescent cells, it is pertinent to propose combination treatments with Bcl-2 family inhibitors acting as senolytic agents to achieve effective Bax and Bak release and senescent cell death.
Senolytic agents other than Bcl-2 family inhibitors may also involve Bcl-2 family proteins in their mechanisms of action. Nintedanib, a tyrosine kinase inhibitor, induces apoptosis in triple-negative breast cancer cells [90], inhibits tumor growth of malignant pleural mesothelioma [91] and non-small cell lung cancer [92] and is one of two US Food and Drug Administration-approved treatments for idiopathic pulmonary fibrosis [93]. The senolytic effect of Nintedanib, which induces Bim expression, as well as the cleavage of caspase 9 and downstream factors caspases 3/7 prominently in senescent cells compared to non-senescent cells, is mediated by signal transducer and activator of transcription 3 (Stat3) inhibition [94]. The inhibition of ubiquitin-specific peptidase 7 selectively induces the apoptosis of senescent cells. The mechanisms of action include the ubiquitination and degradation of the human homolog of Mdm2 and the consequent increase in p53 levels, which, in turn, induces the proapoptotic proteins Puma and Noxa, among others, and inhibits the interaction of Bcl-xL and Bak, selectively inducing apoptosis in senescent cells [95].

References

  1. Chong, S.J.F.; Marchi, S.; Petroni, G.; Kroemer, G.; Galluzzi, L.; Pervaiz, S. Noncanonical Cell Fate Regulation by Bcl-2 Proteins. Trends Cell Biol. 2020, 30, 537–555.
  2. Davoli, T.; Denchi, E.L.; de Lange, T. Persistent Telomere Damage Induces Bypass of Mitosis and Tetraploidy. Cell 2010, 141, 81–93.
  3. Dumontet, C.; Sikic, B.I. Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death. J. Clin. Oncol. 1999, 17, 1061.
  4. Manchado, E.; Guillamot, M.; Malumbres, M. Killing cells by targeting mitosis. Cell Death Differ. 2012, 19, 369–377.
  5. Weaver, B.A.; Cleveland, D.W. Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death. Cancer Cell 2005, 8, 7–12.
  6. Rieder, C.L.; Maiato, H. Stuck in division or passing through: What happens when cells cannot satisfy the spindle assembly checkpoint. Dev. Cell 2004, 7, 637–651.
  7. Valent, A.; Penault-Llorca, F.; Cayre, A.; Kroemer, G. Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: Polyploidization can lead to diagnostic pitfalls with potential impact for clinical management. Cancer Genet. 2013, 206, 37–41.
  8. Malaquin, N.; Vancayseele, A.; Gilbert, S.; Antenor-Habazac, L.; Olivier, M.A.; Ait Ali Brahem, Z.; Saad, F.; Delouya, G.; Rodier, F. DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity. Cells 2020, 9, 1593.
  9. Yosef, R.; Pilpel, N.; Tokarsky-Amiel, R.; Biran, A.; Ovadya, Y.; Cohen, S.; Vadai, E.; Dassa, L.; Shahar, E.; Condiotti, R.; et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 2016, 7, 11190.
  10. Litwiniec, A.; Gackowska, L.; Helmin-Basa, A.; Żuryń, A.; Grzanka, A. Low-dose etoposide-treatment induces endoreplication and cell death accompanied by cytoskeletal alterations in A549 cells: Does the response involve senescence? The possible role of vimentin. Cancer Cell Int. 2013, 13, 9.
  11. Breger, K.S.; Smith, L.; Turker, M.S.; Thayer, M.J. Ionizing Radiation Induces Frequent Translocations with Delayed Replication and Condensation. Cancer Res. 2004, 64, 8231–8238.
  12. Wang, E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995, 55, 2284–2292.
  13. Childs, B.G.; Baker, D.J.; Kirkland, J.L.; Campisi, J.; van Deursen, J.M. Senescence and apoptosis: Dueling or complementary cell fates? EMBO Rep. 2014, 15, 1139–1153.
  14. Fan, Y.; Cheng, J.; Zeng, H.; Shao, L. Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria. Front. Physiol. 2020, 11, 593630.
  15. Drullion, C.; Trégoat, C.; Lagarde, V.; Tan, S.; Gioia, R.; Priault, M.; Djavaheri-Mergny, M.; Brisson, A.A.; Auberger, P.; Mahon, F.-X.; et al. Apoptosis and autophagy have opposite roles on imatinib-induced K562 leukemia cell senescence. Cell Death Dis. 2012, 3, e373.
  16. Rincheval, V.; Renaud, F.; Lemaire, C.; Godefroy, N.; Trotot, P.; Boulo, V.; Mignotte, B.; Vayssiere, J.L. Bcl-2 can promote p53-dependent senescence versus apoptosis without affecting the G1/S transition. Biochem. Biophys. Res. Commun. 2002, 298, 282–288.
  17. López-Diazguerrero, N.E.; López-Araiza, H.; Conde-Perezprina, J.C.; Bucio, L.; Cárdenas-Aguayo, M.C.; Ventura, J.L.; Covarrubias, L.; Gutiérrez-Ruíz, M.C.; Zentella, A.; Königsberg, M. Bcl-2 protects against oxidative stress while inducing premature senescence. Free. Radic. Biol. Med. 2006, 40, 1161–1169.
  18. Sasaki, M.; Kumazaki, T.; Takano, H.; Nishiyama, M.; Mitsui, Y. Senescent cells are resistant to death despite low Bcl-2 level. Mech. Ageing Dev. 2001, 122, 1695–1706.
  19. Vairo, G.; Soos, T.J.; Upton, T.M.; Zalvide, J.; DeCaprio, J.A.; Ewen, M.E.; Koff, A.; Adams, J.M. Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation. Mol. Cell. Biol. 2000, 20, 4745–4753.
  20. Nelyudova, A.; Aksenov, N.D.; Pospelov, V.; Pospelova, T. By Blocking Apoptosis, Bcl-2 in p38-Dependent Manner Promotes Cell Cycle Arrest and Accelerated Senescence After DNA Damage and Serum Withdrawal. Cell Cycle 2007, 6, 2171–2177.
  21. Wang, W.; Wang, D.; Li, H. Initiation of premature senescence by Bcl-2 in hypoxic condition. Int. J. Clin. Exp. Pathol. 2014, 7, 2446–2453.
  22. Schmitt, C.A.; Fridman, J.S.; Yang, M.; Lee, S.; Baranov, E.; Hoffman, R.M.; Lowe, S.W. A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy. Cell 2002, 109, 335–346.
  23. Lee, J.J.; Lee, J.H.; Ko, Y.G.; Hong, S.I.; Lee, J.S. Prevention of premature senescence requires JNK regulation of Bcl-2 and reactive oxygen species. Oncogene 2010, 29, 561–575.
  24. Jemaà, M.; Vitale, I.; Kepp, O.; Berardinelli, F.; Galluzzi, L.; Senovilla, L.; Mariño, G.; Malik, S.A.; Rello-Varona, S.; Lissa, D.; et al. Selective killing of p53-deficient cancer cells by SP600125. EMBO Mol. Med. 2012, 4, 500–514.
  25. Kim, J.A.; Lee, J.; Margolis, R.L.; Fotedar, R. SP600125 suppresses Cdk1 and induces endoreplication directly from G2 phase, independent of JNK inhibition. Oncogene 2010, 29, 1702–1716.
  26. Choi, J.Y.; Shin, H.J.; Bae, I.H. miR-93-5p suppresses cellular senescence by directly targeting Bcl-w and p21. Biochem. Biophys. Res. Commun. 2018, 505, 1134–1140.
  27. Borrás, C.; Mas-Bargues, C.; Román-Domínguez, A.; Sanz-Ros, J.; Gimeno-Mallench, L.; Inglés, M.; Gambini, J.; Viña, J. BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians. Int. J. Mol. Sci. 2020, 21, 418.
  28. Selt, F.; Sigaud, R.; Valinciute, G.; Sievers, P.; Zaman, J.; Alcon, C.; Schmid, S.; Peterziel, H.; Tsai, J.W.; Guiho, R.; et al. BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma. Neuro-Oncol. 2022, noac199.
  29. Ikezawa, K.; Hikita, H.; Shigekawa, M.; Iwahashi, K.; Eguchi, H.; Sakamori, R.; Tatsumi, T.; Takehara, T. Increased Bcl-xL Expression in Pancreatic Neoplasia Promotes Carcinogenesis by Inhibiting Senescence and Apoptosis. Cell. Mol. Gastroenterol. Hepatol. 2017, 4, 185–200.e1.
  30. Jung, M.S.; Jin, D.H.; Chae, H.D.; Kang, S.; Kim, S.C.; Bang, Y.J.; Choi, T.S.; Choi, K.S.; Shin, D.Y. Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation. J. Biol. Chem. 2004, 279, 17765–17771.
  31. Schmitt, E.; Beauchemin, M.; Bertrand, R. Nuclear colocalization and interaction between bcl-xL and cdk1(cdc2) during G2/M cell-cycle checkpoint. Oncogene 2007, 26, 5851–5865.
  32. Hayward, R.L.; MacPherson, J.S.; Cummings, J.; Monia, B.P.; Smyth, J.F.; Jodrell, D.I. Antisense Bcl-xl down-regulation switches the response to topoisomerase I inhibition from senescence to apoptosis in colorectal cancer cells, enhancing global cytotoxicity. Clin. Cancer Res. 2003, 9, 2856–2865.
  33. Tsuji, K.; Kida, Y.; Koshikawa, N.; Yamamoto, S.; Shinozaki, Y.; Watanabe, T.; Lin, J.; Nagase, H.; Takenaga, K. Suppression of non-small-cell lung cancer A549 tumor growth by an mtDNA mutation-targeting pyrrole-imidazole polyamide-triphenylphosphonium and a senolytic drug. Cancer Sci. 2022, 113, 1321–1337.
  34. Rahman, M.; Olson, I.; Mansour, M.; Carlstrom, L.P.; Sutiwisesak, R.; Saber, R.; Rajani, K.; Warrington, A.E.; Howard, A.; Schroeder, M.; et al. Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition. Mol. Cancer Res. 2022, 20, 938–948.
  35. de Carne Trecesson, S.; Guillemin, Y.; Belanger, A.; Bernard, A.C.; Preisser, L.; Ravon, E.; Gamelin, E.; Juin, P.; Barre, B.; Coqueret, O. Escape from p21-mediated oncogene-induced senescence leads to cell dedifferentiation and dependence on anti-apoptotic Bcl-xL and MCL1 proteins. J. Biol. Chem. 2011, 286, 12825–12838.
  36. Bolesta, E.; Pfannenstiel, L.W.; Demelash, A.; Lesniewski, M.L.; Tobin, M.; Schlanger, S.E.; Nallar, S.C.; Papadimitriou, J.C.; Kalvakolanu, D.V.; Gastman, B.R. Inhibition of Mcl-1 Promotes Senescence in Cancer Cells: Implications for Preventing Tumor Growth and Chemotherapy Resistance. Mol. Cell. Biol. 2012, 32, 1879–1892.
  37. Troiani, M.; Colucci, M.; D’Ambrosio, M.; Guccini, I.; Pasquini, E.; Varesi, A.; Valdata, A.; Mosole, S.; Revandkar, A.; Attanasio, G.; et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat. Commun. 2022, 13, 2177.
  38. Jamil, S.; Sobouti, R.; Hojabrpour, P.; Raj, M.; Kast, J.; Duronio, V. A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. Biochem. J. 2005, 387, 659–667.
  39. Whitaker, R.H.; Placzek, W.J. Regulating the BCL2 Family to Improve Sensitivity to Microtubule Targeting Agents. Cells 2019, 8, 346.
  40. Demelash, A.; Pfannenstiel, L.W.; Tannenbaum, C.S.; Li, X.; Kalady, M.F.; DeVecchio, J.; Gastman, B.R. Structure-Function Analysis of the Mcl-1 Protein Identifies a Novel Senescence-regulating Domain. J. Biol. Chem. 2015, 290, 21962–21975.
  41. Demelash, A.; Pfannenstiel, L.W.; Liu, L.; Gastman, B.R. Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence. Oncotarget 2017, 8, 28154–28168.
  42. Forman, K.; Vara, E.; García, C.; Kireev, R.; Cuesta, S.; Acuña-Castroviejo, D.; Tresguerres, J.A.F. Beneficial effects of melatonin on cardiological alterations in a murine model of accelerated aging. J. Pineal Res. 2010, 49, 312–320.
  43. Sanders, Y.Y.; Liu, H.; Zhang, X.; Hecker, L.; Bernard, K.; Desai, L.; Liu, G.; Thannickal, V.J. Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress. Redox Biol. 2013, 1, 8–16.
  44. Alsayegh, K.N.; Gadepalli, V.S.; Iyer, S.; Rao, R.R. Knockdown of CDK2AP1 in Primary Human Fibroblasts Induces p53 Dependent Senescence. PLoS ONE 2015, 10, e0120782.
  45. Werner, L.R.; Huang, S.; Francis, D.M.; Armstrong, E.A.; Ma, F.; Li, C.; Iyer, G.; Canon, J.; Harari, P.M. Small Molecule Inhibition of MDM2–p53 Interaction Augments Radiation Response in Human Tumors. Mol. Cancer Ther. 2015, 14, 1994–2003.
  46. Li, P.; Zhao, M.; Parris, A.B.; Feng, X.; Yang, X. p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochem. Biophys. Res. Commun. 2015, 464, 1267–1274.
  47. Zhang, H.; Zhang, X.; Li, X.; Meng, W.; Bai, Z.; Rui, S.; Wang, Z.; Zhou, W.; Jin, X. Effect of CCNB1 silencing on cell cycle, senescence, and apoptosis through the p53 signaling pathway in pancreatic cancer. J. Cell. Physiol. 2018, 234, 619–631.
  48. Zhao, S.; Zhao, Z.-J.; He, H.-Y.; Wu, J.-C.; Ding, X.-Q.; Yang, L.; Jia, N.; Li, Z.-J.; Zheng, H.-C. The roles of ING5 in gliomas: A good marker for tumorigenesis and a potential target for gene therapy. Oncotarget 2017, 8, 56558–56568.
  49. Baar, M.P.; Brandt, R.M.C.; Putavet, D.A.; Klein, J.D.D.; Derks, K.W.J.; Bourgeois, B.R.M.; Stryeck, S.; Rijksen, Y.; Van Willigenburg, H.; Feijtel, D.A.; et al. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 2017, 169, 132–147.e16.
  50. Tsukamoto, H.; Huston, G.E.; Dibble, J.; Duso, D.K.; Swain, S.L. Bim Dictates Naive CD4 T Cell Lifespan and the Development of Age-Associated Functional Defects. J. Immunol. 2010, 185, 4535–4544.
  51. Schmidt, S.; Schneider, L.; Essmann, F.; Cirstea, I.C.; Kuck, F.; Kletke, A.; Jänicke, R.U.; Wiek, C.; Hanenberg, H.; Ahmadian, M.R.; et al. The centrosomal protein TACC3 controls paclitaxel sensitivity by modulating a premature senescence program. Oncogene 2010, 29, 6184–6192.
  52. Gonçalves, J.; Emmons, M.F.; Faião-Flores, F.; Aplin, A.E.; Harbour, J.W.; Licht, J.D.; Wink, M.R.; Smalley, K.S.M.; Avezedo, J.G. Decitabine limits escape from MEK inhibition in uveal melanoma. Pigment. Cell Melanoma Res. 2020, 33, 507–514.
  53. Zhang, J.; Patel, J.M.; Block, E.R. Enhanced apoptosis in prolonged cultures of senescent porcine pulmonary artery endothelial cells. Mech. Ageing Dev. 2002, 123, 613–625.
  54. Stickles, X.B.; Marchion, D.C.; Bicaku, E.; AL Sawah, E.; Abbasi, F.; Xiong, Y.; Zgheib, N.B.; Boac, B.M.; Orr, B.C.; Judson, P.L.; et al. BAD-mediated apoptotic pathway is associated with human cancer development. Int. J. Mol. Med. 2015, 35, 1081–1087.
  55. Lin, X.; Zhan, J.K.; Zhong, J.Y.; Wang, Y.J.; Wang, Y.; Li, S.; He, J.Y.; Tan, P.; Chen, Y.Y.; Liu, X.B.; et al. lncRNA-ES3/miR-34c-5p/BMF axis is involved in regulating high-glucose-induced calcification/senescence of VSMCs. Aging 2019, 11, 523–535.
  56. Zhuang, L.; Ly, R.; Rösl, F.; Niebler, M. p53 Is Regulated in a Biphasic Manner in Hypoxic Human Papillomavirus Type 16 (HPV16)-Positive Cervical Cancer Cells. Int. J. Mol. Sci. 2020, 21, 9533.
  57. Capparelli, C.; Guido, C.; Whitaker-Menezes, D.; Bonuccelli, G.; Balliet, R.; Pestell, T.G.; Goldberg, A.F.; Pestell, R.G.; Howell, A.; Sneddon, S.; et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis, via glycolysis and ketone production. Cell Cycle 2012, 11, 2285–2302.
  58. Cho, S.I.; Jo, E.-R.; Song, H. Urolithin A attenuates auditory cell senescence by activating mitophagy. Sci. Rep. 2022, 12, 7704.
  59. Ewald, J.A.; Desotelle, J.A.; Wilding, G.; Jarrard, D.F. Therapy-Induced Senescence in Cancer. J. Natl. Cancer Inst. 2010, 102, 1536–1546.
  60. Saleh, T.; Carpenter, V.J.; Bloukh, S.; Gewirtz, D.A. Targeting tumor cell senescence and polyploidy as potential therapeutic strategies. Semin. Cancer Biol. 2022, 81, 37–47.
  61. Niedernhofer, L.J.; Robbins, P.D. Senotherapeutics for healthy ageing. Nat. Rev. Drug Discov. 2018, 17, 377.
  62. Kim, E.-C.; Kim, J.-R. Senotherapeutics: Emerging strategy for healthy aging and age-related disease. BMB Rep. 2019, 52, 47–55.
  63. Zhang, L.; Pitcher, L.E.; Prahalad, V.; Niedernhofer, L.J.; Robbins, P.D. Targeting cellular senescence with senotherapeutics: Senolytics and senomorphics. FEBS J. 2022, 290, 1362–1383.
  64. Rysanek, D.; Vasicova, P.; Kolla, J.N.; Sedlak, D.; Andera, L.; Bartek, J.; Hodny, Z. Synergism of BCL-2 family inhibitors facilitates selective elimination of senescent cells. Aging 2022, 14, 6381–6414.
  65. Souers, A.J.; Leverson, J.D.; Boghaert, E.R.; Ackler, S.L.; Catron, N.D.; Chen, J.; Dayton, B.D.; Ding, H.; Enschede, S.H.; Fairbrother, W.J.; et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013, 19, 202–208.
  66. Tse, C.; Shoemaker, A.R.; Adickes, J.; Anderson, M.G.; Chen, J.; Jin, S.; Johnson, E.F.; Marsh, K.C.; Mitten, M.J.; Nimmer, P.; et al. ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor. Cancer Res. 2008, 68, 3421–3428.
  67. Lafontaine, J.; Cardin, G.; Malaquin, N.; Boisvert, J.-S.; Rodier, F.; Wong, P. Senolytic Targeting of Bcl-2 Anti-Apoptotic Family Increases Cell Death in Irradiated Sarcoma Cells. Cancers 2021, 13, 386.
  68. Yamamoto, M.; Suzuki, S.; Togashi, K.; Sugai, A.; Okada, M.; Kitanaka, C. Gemcitabine Cooperates with Everolimus to Inhibit the Growth of and Sensitize Malignant Meningioma Cells to Apoptosis Induced by Navitoclax, an Inhibitor of Anti-Apoptotic BCL-2 Family Proteins. Cancers 2022, 14, 1706.
  69. Yamamoto, M.; Sanomachi, T.; Suzuki, S.; Togashi, K.; Sugai, A.; Seino, S.; Sato, A.; Okada, M.; Kitanaka, C. Gemcitabine radiosensitization primes irradiated malignant meningioma cells for senolytic elimination by navitoclax. Neuro-Oncol. Adv. 2021, 3, vdab148.
  70. Qing, Y.; Li, H.; Zhao, Y.; Hu, P.; Wang, X.; Yu, X.; Zhu, M.; Wang, H.; Wang, Z.; Guo, Q.; et al. One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence. Oxidative Med. Cell. Longev. 2021, 2021, 5529518.
  71. Muenchow, A.; Weller, S.; Hinterleitner, C.; Malenke, E.; Bugl, S.; Wirths, S.; Müller, M.R.; Schulze-Osthoff, K.; Aulitzky, W.E.; Kopp, H.-G.; et al. The BCL-2 selective inhibitor ABT-199 sensitizes soft tissue sarcomas to proteasome inhibition by a concerted mechanism requiring BAX and NOXA. Cell Death Dis. 2020, 11, 701.
  72. Zhu, Y.; Tchkonia, T.; Fuhrmann-Stroissnigg, H.; Dai, H.M.; Ling, Y.Y.; Stout, M.B.; Pirtskhalava, T.; Giorgadze, N.; Johnson, K.O.; Giles, C.B.; et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016, 15, 428–435.
  73. Chang, J.; Wang, Y.; Shao, L.; Laberge, R.-M.; DeMaria, M.; Campisi, J.; Janakiraman, K.; Sharpless, N.E.; Ding, S.; Feng, W.; et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 2016, 22, 78–83.
  74. Saleh, T.; Carpenter, V.J.; Tyutyunyk-Massey, L.; Murray, G.; Leverson, J.D.; Souers, A.J.; Alotaibi, M.R.; Faber, A.C.; Reed, J.; Harada, H.; et al. Clearance of therapy-induced senescent tumor cells by the senolytic ABT-263 via interference with BCL-X(L) -BAX interaction. Mol. Oncol. 2020, 14, 2504–2519.
  75. Shahbandi, A.; Rao, S.G.; Anderson, A.Y.; Frey, W.D.; Olayiwola, J.O.; Ungerleider, N.A.; Jackson, J.G. BH3 mimetics selectively eliminate chemotherapy-induced senescent cells and improve response in TP53 wild-type breast cancer. Cell Death Differ. 2020, 27, 3097–3116.
  76. Kline, M.P.; Rajkumar, S.V.; Timm, M.M.; Kimlinger, T.K.; Haug, J.L.; Lust, J.A.; Greipp, P.R.; Kumar, S. ABT-737, an inhibitor of Bcl-2 family proteins, is a potent inducer of apoptosis in multiple myeloma cells. Leukemia 2007, 21, 1549–1560.
  77. Kolodkin-Gal, D.; Roitman, L.; Ovadya, Y.; Azazmeh, N.; Assouline, B.; Schlesinger, Y.; Kalifa, R.; Horwitz, S.; Khalatnik, Y.; Hochner-Ger, A.; et al. Senolytic elimination of Cox2-expressing senescent cells inhibits the growth of premalignant pancreatic lesions. Gut 2022, 71, 345–355.
  78. Beltzig, L.; Christmann, M.; Kaina, B. Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics. Cells 2022, 11, 2588.
  79. Schwarzenbach, C.; Tatsch, L.; Vilar, J.B.; Rasenberger, B.; Beltzig, L.; Kaina, B.; Tomicic, M.; Christmann, M. Targeting c-IAP1, c-IAP2, and Bcl-2 Eliminates Senescent Glioblastoma Cells Following Temozolomide Treatment. Cancers 2021, 13, 3585.
  80. Moncsek, A.; Al-Suraih, M.S.; Trussoni, C.E.; O’Hara, S.P.; Splinter, P.L.; Zuber, C.; Patsenker, E.; Valli, P.V.; Fingas, C.D.; Weber, A.; et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2(−/−)) mice. Hepatology 2018, 67, 247–259.
  81. Wu, G.; Zhang, C.; Xu, L.; Chen, H.; Fan, X.; Sun, B.; Tang, Q.; Zhan, Y.; Chen, T.; Wang, X. BAK plays a key role in A-1331852-induced apoptosis in senescent chondrocytes. Biochem. Biophys. Res. Commun. 2022, 609, 93–99.
  82. Leverson, J.D.; Phillips, D.C.; Mitten, M.J.; Boghaert, E.R.; Diaz, D.; Tahir, S.K.; Belmont, L.D.; Nimmer, P.; Xiao, Y.; Ma, X.M.; et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci. Transl. Med. 2015, 7, 279ra40.
  83. Wang, L.; Doherty, G.A.; Judd, A.S.; Tao, Z.F.; Hansen, T.M.; Frey, R.R.; Song, X.; Bruncko, M.; Kunzer, A.R.; Wang, X.; et al. Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-X(L) Inhibitor. ACS Med. Chem. Lett. 2020, 11, 1829–1836.
  84. Wu, G.; Li, X.; Zhan, Y.; Fan, X.; Xu, L.; Chen, T.; Wang, X. BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells. Biochem. Biophys. Res. Commun. 2022, 627, 160–167.
  85. Zhu, Y.; Doornebal, E.J.; Pirtskhalava, T.; Giorgadze, N.; Wentworth, M.; Fuhrmann-Stroissnigg, H.; Niedernhofer, L.J.; Robbins, P.D.; Tchkonia, T.; Kirkland, J.L. New agents that target senescent cells: The flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 2017, 9, 955–963.
  86. Song, S.; Kim, S.; El-Sawy, E.; Cerella, C.; Orlikova-Boyer, B.; Kirsch, G.; Christov, C.; Dicato, M.; Diederich, M. Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477. Mar. Drugs 2021, 19, 285.
  87. Bougie, P.G.; Maiga, S.; Tessoulin, B.; Bourcier, J.; Bonnet, A.; Rodriguez, M.S.; Le Gouill, S.; Touzeau, C.; Moreau, P.; Pellat-Deceunynck, C.; et al. BH3-mimetic toolkit guides the respective use of BCL2 and MCL1 BH3-mimetics in myeloma treatment. Blood 2018, 132, 2656–2669.
  88. Senichkin, V.V.; Pervushin, N.V.; Zamaraev, A.V.; Sazonova, E.V.; Zuev, A.P.; Streletskaia, A.Y.; Prikazchikova, T.A.; Zatsepin, T.S.; Kovaleva, O.V.; Tchevkina, E.M.; et al. Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors. Cancers 2021, 14, 181.
  89. Wei, A.H.; Roberts, A.W.; Spencer, A.; Rosenberg, A.S.; Siegel, D.; Walter, R.B.; Caenepeel, S.; Hughes, P.; McIver, Z.; Mezzi, K.; et al. Targeting MCL-1 in hematologic malignancies: Rationale and progress. Blood Rev. 2020, 44, 100672.
  90. Liu, C.-Y.; Huang, T.-T.; Chu, P.-Y.; Huang, C.-T.; Lee, C.-H.; Wang, W.-L.; Lau, K.-Y.; Tsai, W.-C.; Chao, T.-I.; Su, J.-C.; et al. The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells. Exp. Mol. Med. 2017, 49, e366.
  91. Laszlo, V.; Valko, Z.; Kovacs, I.; Ozsvar, J.; Hoda, M.A.; Klikovits, T.; Lakatos, D.; Czirok, A.; Garay, T.; Stiglbauer, A.; et al. Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth In Vivo. Clin. Cancer Res. 2018, 24, 3729–3740.
  92. Shiratori, T.; Tanaka, H.; Tabe, C.; Tsuchiya, J.; Ishioka, Y.; Itoga, M.; Taima, K.; Takanashi, S.; Tasaka, S. Effect of nintedanib on non-small cell lung cancer in a patient with idiopathic pulmonary fibrosis: A case report and literature review. Thorac. Cancer 2020, 11, 1720–1723.
  93. Kato, K.; Shin, Y.-J.; Palumbo, S.; Papageorgiou, I.; Hahn, S.; Irish, J.D.; Rounseville, S.P.; Krafty, R.T.; Wollin, L.; Sauler, M.; et al. Leveraging ageing models of pulmonary fibrosis: The efficacy of nintedanib in ageing. Eur. Respir. J. 2021, 58, 2100759.
  94. Cho, H.-J.; Hwang, J.-A.; Yang, E.J.; Kim, E.-C.; Kim, J.-R.; Kim, S.Y.; Kim, Y.Z.; Park, S.C.; Lee, Y.-S. Nintedanib induces senolytic effect via STAT3 inhibition. Cell Death Dis. 2022, 13, 760.
  95. He, Y.; Li, W.; Lv, D.; Zhang, X.; Zhang, X.; Ortiz, Y.T.; Budamagunta, V.; Campisi, J.; Zheng, G.; Zhou, D. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell 2020, 19, e13117.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Physiology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Daniel Barriuso
,
Lucia Alvarez-Frutos
,
Lucia Gonzalez-Gutierrez
,
Omar Motiño
,
Guido Kroemer
,
Roberto Palacios-Ramirez
,
Laura Senovilla
View Times: 680
Revisions: 2 times (View History)
Update Date: 17 Apr 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Academic Video Service
    Feedback