A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC

Samaraweera, Leleesha; Adomako, Alfred; Rodriguez-Gabin, Alicia; McDaid, Hayley M.

doi:10.1038/s41598-017-01964-1

Cited by 143 publications

(96 citation statements)

References 45 publications

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“…Piperlongumine -Radiation-induced senescent astrocytes in vivo -Radiation-induced cognitive dysfunction mouse model [205] -SMARCB1 downregulation-induced senescent A375 melanoma cells -Therapy-induced A549 or H358 lung cancer cells [145] -Radiation-induced, replication exhausted and Ras-induced senescent WI38 fibroblasts [206] Curcumin -Patient-derived senescent intervertebral disc cells [207] -Radiation-induced, oncogene-induced and replication-exhausted senescent WI38 fibroblasts [208] Fisetin -Replication-exhausted senescent Ercc1−/− MEFs -Therapy-induced senescent IMR90 senescent cells -Progeroid Ercc1 −/∆ mice and aged C57BL/6 mouse models -Murine and human-derived senescent adipose tissue [209] -Senescent human umbilical vein endothelial cells [210] Metformin -Murine olfactory ensheathing cells ex vivo [211] Panobinostat -Therapy-induced senescent A549 lung and FaDu head and neck cancer cells [212] 17-DMAG -Oxidative-stress-induce primary Ercc1 −/− -progeroid Ercc1 −/∆ mouse model [213] Torin 1 -Murine senescent hepatocytes ex vivo [214] Epigallocatechin gallate (EGCG) -Senescent 3T3-L1 preadipocytes [215] Bafilomycin A1 -Therapy-induced HCT116 colorectal cancer cells [158] Azithromycin and roxithromycin -Therapy-induced senescent MRC-5 and BJ human fibroblasts [216] Fenofibrate -Senescent T/C28a2 human chondrocytes [217] Cardiac glycosides -Therapy-induced senescent A549 lung cancer cells and SK-MEL-103 melanoma cells in vitro and in vivo [218,219] Several natural and synthetic compounds have been tested for their senescence-eliminating effects in a variety of disease models. The table summarizes the primary current preclinical evidence demonstrating the senolytic agent and the experimental model used.…”

Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

“…The histone deacetylase (HDAC) inhibitor panobinostat, was investigated for its potential to clear lung, head and neck cancer cells induced into senescence by cisplatin or paclitaxel in vitro [212]. Chemotherapy-induced senescent tumor cells were more vulnerable to the toxic effects of panobinostat in comparison to their proliferating counterparts [212]. Interestingly, the senolytic activity of panobinostat was also linked to its effect on Bcl-xL expression levels [212].…”

Section: Panobinostatmentioning

confidence: 99%

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Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

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For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

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Section: Senolytic Model/cell Line Referencementioning

confidence: 99%

Section: Panobinostatmentioning

confidence: 99%

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Saleh

Bloukh

Carpenter

et al. 2020

Cancers

206

150

View full text Add to dashboard Cite

show abstract

“…Senescence is a common outcome of many FDA-approved interventions and occurs in both tumor and nontumor cells, thus limiting the anticancer efficacy of cycle-dependent cancer therapeutics. 9 Furthermore, spontaneous reversion of senescent cancer cells can propel tumors toward an aggressive, recalcitrant state, 2,10,11 while recent studies have demonstrated that chemotherapy-mediated senescence in nonmalignant cells contributes to cumulative toxicity. 12 However, contemporary drug screening programs do not typically screen for senescence as a clinically relevant end point.…”

mentioning

confidence: 99%

Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

et al. 2018

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(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide.

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“…PBA, an adjuvant to radiotherapy for DMBA‐induced OSCC, prevented radiation‐induced oral mucositis and suppressed oral carcinogenesis (Chung et al, ). Synergy following LBH589 and CDDP or Taxol in HNSCC cell lines was associated with decreased H3ac and increased Bcl‐xL‐mediated senescence, indicating the possible senolytic effect of LBH589 (Samaraweera, Adomako, Rodriguez‐Gabin, & McDaid, ). The multitargeted inhibitor of EGFR/ERBB2/HDACs CUDC‐101 combined with radiation and CDDP may exert anticancer activity.…”

Section: Combined Treatment Of Epigenetic Regulators and Other Cancermentioning

confidence: 99%

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

et al. 2019

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Oral squamous cell carcinoma (OSCC) is a common malignancy with dismal prognosis without effective therapeutic options in advanced cases. The evolution from oral potentially malignant disorders to OSCC has poorly described underlying epigenetic features. With the ability of silencing or activation of vital genes, histone modifications’ and modifiers’ potentiality for early diagnosis, prognosis predicting, and therapy in OSCC were evaluated by extensive epigenetic studies. This review investigates the roles of dysregulated histone modifications and the associated modifying enzymes in OSCC onset and progression. Also, we focus on the current advances of histone modifications as therapeutic targets and the potential value of epi‐drugs.

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A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC

Cited by 143 publications

References 45 publications

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Therapy-Induced Senescence: An “Old” Friend Becomes the Enemy

Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

Histone modifications in oral squamous cell carcinoma and oral potentially malignant disorders

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