Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3

Leeman‐Neill, Rebecca J.; Wheeler, Sarah; Singh, Shivendra V.; Thomas, Sufi M.; Seethala, Raja R.; Neill, Daniel B.; Panahandeh, Mary; Hahm, Eun Ryeong; Joyce, Sonali; Sen, Malabika; Cai, Quan; Freilino, Maria L.; Li, Changyou; Johnson, Daniel E.; Grandis, Jennifer R.

doi:10.1093/carcin/bgp211

Cited by 95 publications

(78 citation statements)

References 40 publications

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“…In a xenograft model of HNSCC, GS treatment resulted in increased apoptosis and decreased expression of STAT3. Therefore, these results suggest that the inhibition of STAT3 and HIF-1α by GS provide a strong rationale for further clinical investigation of this compound in the treatment of HNSCC [263][264][265]. Moreover, the reported safety of GS [266] makes it a good candidate for complementary and preventive therapy.…”

Section: Guggulsteronementioning

confidence: 97%

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Siveen

Sikka

Surana

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

479

510

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Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling that is usually generated at cell surface receptors and thereby transmit it to the nucleus. Numerous studies have demonstrated constitutive activation of STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias, lymphomas, and multiple myeloma) as well as diverse solid tumors (such as head and neck, breast, lung, gastric, hepatocellular, colorectal and prostate cancers). There is strong evidence to suggest that aberrant STAT3 signaling promotes initiation and progression of human cancers by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation results in the induction of apoptosis in tumor cells, and accordingly its pharmacological modulation by tyrosine kinase inhibitors, antisense oligonucleotides, decoy nucleotides, dominant negative proteins, RNA interference and chemopreventive agents have been employed to suppress the proliferation of various human cancer cells in culture and tumorigenicity in vivo. However, the identification and development of novel drugs that can target deregulated STAT3 activation effectively remains an important scientific and clinical challenge. This review presents the evidence for critical roles of STAT3 in oncogenesis and discusses the potential for development of novel cancer therapies based on mechanistic understanding of STAT3 signaling cascade.

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Section: Guggulsteronementioning

confidence: 97%

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Siveen

Sikka

Surana

et al. 2014

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

479

510

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“…Based on these pharmacokinetic observations, it is possible that the concentrations of GL needed to inhibit cancer cell growth may be achievable in humans. More recently (Leeman-Neill et al, 2009), we reported that treatment with GL (3 mol standardized to zGug, daily for 3 weeks) resulted in the enhancement of cetuximab activity in xenograft model of head and neck cancer.…”

Section: Discussionmentioning

confidence: 97%

Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase

Xiao¹,

Zeng²,

Prakash³

et al. 2010

Mol Pharmacol

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Gugulipid (GL), extract of Indian Ayurvedic medicinal plantCommiphora mukul, has been used to treat a variety of ailments. We report an anticancer effect and mechanism of GL against human prostate cancer cells. Treatment with GL significantly inhibited the viability of human prostate cancer cell line LNCaP (androgen-dependent) and its androgen-independent variant (C81) with an IC 50 of ϳ1 M (24-h treatment), at pharmacologically relevant concentrations standardized to its major active constituent z-guggulsterone. The GL-induced growth inhibition correlated with apoptosis induction as evidenced by an increase in cytoplasmic histone-associated DNA fragmentation and sub-G 0 /G 1 -DNA fraction, and cleavage of poly(ADPribose) polymerase. The GL-induced apoptosis was associated with reactive oxygen species (ROS) production and c-Jun NH 2 -terminal kinase (JNK) activation. The induction of proapoptotic Bcl-2 family proteins Bax and Bak and a decrease of antiapoptotic Bcl-2 protein Bcl-2 were observed in GL-treated cells. SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double-knockout mice were significantly more resistant to GL-induced cell killing compared with wild-type cells. It is interesting to note that a representative normal prostate epithelial cell line (PrEC) was relatively more resistant to GL-mediated cellular responses compared with prostate cancer cells. The GL treatment caused the activation of JNK that functioned upstream of Bax activation in apoptosis response. The GL-induced conformational change of Bax and apoptosis were significantly suppressed by genetic suppression of JNK activation. In conclusion, the present study indicates that ROSdependent apoptosis by GL is regulated by JNK signaling axis.

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“…4). Based on these data, the remaining HCS operation runs (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) were conducted in Cal33 cells with passage #s <20 and with IL-6 that had been reconstituted and stored at -80°C for £4 weeks.…”

Section: ‰ Hcs For Inhibitors Of Il-6-induced Pstat3mentioning

confidence: 99%

“…1,2,4,[6][7][8] Head and neck squamous cell carcinoma (HNSCC) tumors and cell lines exhibit high pSTAT3-Y705 expression levels. 4,5,[7][8][9][10][11] HNSCC is the eighth leading cause of cancer worldwide with an incidence of *600,000 new cases and *300,000 deaths per annum. [12][13][14] Smoking, alcohol use, genetics, and human papillomavirus (HPV) infection contribute to the carcinogenesis and pathology of HNSCC.…”

Section: Introductionmentioning

confidence: 99%

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

Johnston

Sen

Hua

et al. 2015

ASSAY and Drug Development Technologies

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Signal transducer and activator of transcription factor 3 (STAT3) is hyperactivated in head and neck squamous cell carcinomas (HNSCC). Cumulative evidence indicates that IL-6 production by HNSCC cells and/or stromal cells in the tumor microenvironment activates STAT3 and contributes to tumor progression and drug resistance. A library of 94,491 compounds from the Molecular Library Screening Center Network (MLSCN) was screened for the ability to inhibit interleukin-6 (IL-6)-induced pSTAT3 activation. For contractual reasons, the primary high-content screening (HCS) campaign was conducted over several months in 3 distinct phases; 1,068 (1.1%) primary HCS actives remained after cytotoxic or fluorescent outliers were eliminated. One thousand one hundred eighty-seven compounds were cherry-picked for confirmation; actives identified in the primary HCS and compounds selected by a structural similarity search of the remaining MLSCN library using hits identified in phases I and II of the screen. Actives were confirmed in pSTAT3 IC 50 assays, and an IFNc-induced pSTAT1 activation assay was used to prioritize selective inhibitors of STAT3 activation that would not inhibit STAT1 tumor suppressor functions. Two hundred three concentration-dependent inhibitors of IL-6-induced pSTAT3 activation were identified and 89 of these also produced IC 50 s against IFN-c-induced pSTAT1 activation. Forty-nine compounds met our hit criteria: they reproducibly inhibited IL-6-induced pSTAT3 activation by ‡70% at 20 lM; their pSTAT3 activation IC 50 s were £25 lM; they were ‡2-fold selective for pSTAT3 inhibition over pSTAT1 inhibition; a cross target query of PubChem indicated that they were not biologically promiscuous; and they were ‡90% pure. Twenty-six chemically tractable hits that passed filters for nuisance compounds and had acceptable drug-like and ADME-Tox properties by computational evaluation were purchased for characterization. The hit structures were distributed among 5 clusters and 8 singletons. Twenty-four compounds inhibited IL-6-induced pSTAT3 activation with IC 50 s £20 lM and 13 were ‡3-fold selective versus inhibition of pSTAT1 activation. Eighteen hits inhibited the growth of HNSCC cell lines with average IC 50 s £ 20 lM. Four chemical series were progressed into lead optimization: the guanidinoquinazolines, the triazolothiadiazines, the amino alcohols, and an oxazole-piperazine singleton.

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Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3

Cited by 95 publications

References 40 publications

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase

HCS Campaign to Identify Selective Inhibitors of IL-6-Induced STAT3 Pathway Activation in Head and Neck Cancer Cell Lines

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