Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling

Wang, Lingzhi; Syn, Nicholas; Subhash, Vinod Vijay; Any, Yijia; Thuya, Win Lwin; Cheow, Esther Sok Hwee; Kong, Li Ren; Yu, F.; Peethala, Praveen C.; Wong, Andrea Li‐Ann; Laljibhai, Hirpara J.; Chinnathambi, Arunachalam; Ong, Pei Shi; Ho, Paul C.; Sethi, Gautam; Yong, Wei Peng; Goh, Boon Cher

doi:10.1016/j.canlet.2017.12.030

Cited by 70 publications

(42 citation statements)

References 36 publications

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“…Aberrant expression of histone deacetylases (HDACs) is a hallmark of numerous types of cancer, and is involved in mediating the proliferation, migration, invasion and genotoxic chemotherapy resistance of cancer cells (20). HDACs are potential anticancer drug targets that may be used to treat patients with lung cancer (21,22).…”

Section: Introductionmentioning

confidence: 99%

Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis

Sang

Sun

et al. 2019

Int J Oncol

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Plakoglobin is a tumor suppressor gene in lung cancer; however, the mechanism by which it is downregulated in lung cancer is largely unknown. The aim of the present study was to investigate whether histone deacetylases (HDACs) regulate plakoglobin expression in lung cancer. The effects of overexpression or knockdown of HDAC7 on plakoglobin were determined using stably transfected lung cancer cell lines. Chromatin immunoprecipitation assays were performed to elucidate the mechanisms underlying the HDAC7-induced suppression of plakoglobin. A Cell Counting Kit-8 and Transwell assays were performed, and a nude mouse in vivo model was established to investigate the role of the HDAC7/plakoglobin pathway in cell migration, invasion and metastasis. Ectopic expression of HDAC7 was identified to suppress mRNA and protein levels of plakoglobin in lung cancer cells, whereas silencing HDAC7 with short hairpin RNA increased the expression of plakoglobin. HDAC7 was proposed to suppressed plakoglobin by directly binding to its promoter. Overexpression or knockdown of HDAC7 promoted or inhibited cell proliferation, migration and invasion, respectively. Furthermore, knockdown of HDAC7 significantly suppressed tumor growth and metastasis in vivo. In addition, overexpression of plakoglobin significantly reduced the enhanced cell proliferation, migration and invasion induced by ectopic HDAC7. In conclusion, suppression of plakoglobin by HDAC7 promoted the proliferation, migration, invasion and metastasis in lung cancer. This novel axis of HDAC7/ plakoglobin may be valuable in the development of novel therapeutic strategies for treating patients with lung cancer.

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Section: Introductionmentioning

confidence: 99%

Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis

Sang

Sun

et al. 2019

Int J Oncol

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“…Despite the choice of carboplatin 40 is favored in terms of toxicity, its lower potency requires the combination with other drugs to increase its anticancer activity. Recently, Wang et al proposed to combine carboplatin 40 with panobinostat 6 getting a strong improvement in cell proliferation reduction with IC 50 values ranging between 4 and 21 nM in different NSCLC cell lines such as H460, H226, A549, Calu‐1, and SKMES‐1. These promising outcomes are likely the result of the pleiotropic effects of panobinostat 6 which, in addition to the modulation of histone acetylation, has also hyperacetylating effects on non‐Histone substrates including proteins that play a fundamental role in carcinogenesis such as signal transducer and activator of transcription 3 (STAT3), heat‐shock protein 90 (HSP90), p53, E2F, nuclear factor‐kB (NF‐kB), c‐Myc, and HIF‐1α .…”

Section: The Mmt Approachmentioning

confidence: 99%

“…Tumorigenic mouse models also confirm the chemo sensitizer effect induced by panobinostat 6 . Indeed, the carboplatin 40 /panobinostat 6 combination (Combination F, Figure ) led to a markedly stalled disease progression by 92% compared to the negative controls, that also resulted greater than that caused by carboplatin 40 (28%) or panobinostat 6 (54%) alone …”

Section: The Mmt Approachmentioning

confidence: 99%

“…Indeed, the carboplatin 40/panobinostat 6 combination (Combination F, Figure 3) led to a markedly stalled disease progression by 92% compared to the negative controls, that also resulted greater than that caused by carboplatin 40 (28%) or panobinostat 6 (54%) alone. 139 To date, only a few effective therapeutic options for the treatment of NRAS-driven melanoma are available. 146 A lot of clinical studies have been conducted focusing on RAS effectors, in particular on inhibitors of PI3K signaling pathways 147 and of mitogen-activated protein kinase (MAPK) such as MEK inhibitors, 147 Recently, other preclinical studies based on the simultaneous administration of BETi and HDACi in melanoma cells as well as in murine models of pancreatic ductal adenocarcinoma have been described recently.…”

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confidence: 99%

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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“…Lung cancer is the second most common type of cancer in both sexes and a leading cause of cancer-related deaths [1][2][3][4]. Non-small cell lung cancer (NSCLC) and small cell lung carcinoma are the two major subtypes, which account for about 80-85% and 10-15% of all lung cancer, respectively [5][6][7][8][9][10]. The development and progression of NSCLC are tightly associated with smoking, exposure to asbestos and radon, drinking of arsenic-contaminated water, family history, and inhalation of carcinogens, such as beryllium, mustard gas, cadmium, nickel, etc.…”

Section: Introductionmentioning

confidence: 99%

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

et al. 2019

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STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented.In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

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Pan-HDAC inhibition by panobinostat mediates chemosensitization to carboplatin in non-small cell lung cancer via attenuation of EGFR signaling

Cited by 70 publications

References 36 publications

Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis

Histone deacetylase 7 inhibits plakoglobin expression to promote lung cancer cell growth and metastasis

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

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