AT-101 inhibits hedgehog pathway activity and cancer growth

Wang, Juan; Peng, Yuanqiu; Liu, Yuan; Yang, Jun; Huang, Ming Te; Tan, Wenfu

doi:10.1007/s00280-015-2812-x

Cited by 18 publications

(17 citation statements)

References 48 publications

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“…Given the frequent dysregulation of BCL-2 and p53 in R/M HNSCC[30], therapy with BH3 mimetics has the potential to inhibit the hedgehog pathway, inhibit angiogenesis, augment chemotherapy induced apoptosis, and reverse chemoresistance[16,18,31,32]. Previous in vitro studies have demonstrated this activity[33,32,34], including in HNSCC cell lines[18].…”

Section: Discussionmentioning

confidence: 99%

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A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

et al. 2016

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Background AT-101 is a BCL-2 Homolog domain 3 mimetic previously demonstrated to have tumoricidal effects in advanced solid organ malignancies. Given the evidence of activity in xenograft models, treatment with AT-101 in combination with docetaxel is a therapeutic doublet of interest in metastatic head and neck squamous cell carcinoma. Patients and Methods Patients included in this trial had unresectable, recurrent, or distantly metastatic head and neck squamous cell carcinoma (R/M HNSCC) not amenable to curative radiation or surgery. This was an open label randomized, phase II trial in which patients were administered AT-101 in addition to docetaxel. The three treatment arms were docetaxel, docetaxel plus pulse dose AT-101, and docetaxel plus metronomic dose AT-101. The primary endpoint of this trial was overall response rate. Results Thirty-five patients were registered and 32 were evaluable for treatment response. Doublet therapy with AT-101 and docetaxel was well tolerated with only 2 patients discontinuing therapy due to treatment related toxicities. The overall response rate was 11% (4 partial responses) with a clinical benefit rate of 74%. Median progression free survival was 4.3 months (range: 0.7–13.7) and overall survival was 5.5 months (range: 0.4–24). No significant differences were noted between dosing strategies. Conclusion Although met with a favorable toxicity profile, the addition of AT-101 to docetaxel in R/M HNSCC does not appear to demonstrate evidence of efficacy.

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Section: Discussionmentioning

confidence: 99%

“…Previous in vitro studies have demonstrated this activity[33,32,34], including in HNSCC cell lines[18]. However, results regarding the clinical efficacy of AT-101 have been mixed with various trials showing both efficacy[26,25] and futility[24,27,35] in varying malignancies.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

et al. 2016

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“…Ko et al showed that an intraperitoneal injection of gossypol or gossypol acetic acid (GAA) (5-10 mg/ kg) significantly reduced the growth of colorectal carcinoma induced by a subcutaneous injection of COLO205 cells in nude mice (Ko et al 2007). Moreover, a recent study demonstrated the in vivo antitumoral activity of orally (À)-GOS (20-40 mg/kg) in a mouse model of medulloblastoma (Wang et al 2015). Several in vivo studies investigated the activity of gossypol in prostate cancer xenograft model in nude mice.…”

Section: Discussionmentioning

confidence: 99%

(±)-Gossypol induces apoptosis and autophagy in head and neck carcinoma cell lines and inhibits the growth of transplanted salivary gland cancer cells in BALB/c mice

Benvenuto

Mattera

Masuelli

et al. 2016

International Journal of Food Sciences and Nutrition

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Racemic Gossypol [(±)-GOS], composed of both (-)-GOS and (+)-GOS, is a small BH3-mimetic polyphenol derived from cotton seeds. (±)-GOS has been employed and well tolerated by cancer patients. Head and neck carcinoma (HNC) represents one of the most fatal cancers worldwide, and a significant proportion of HNC expresses high levels of antiapoptotic Bcl-2 proteins. In this study, we demonstrate that (±)-GOS inhibits cell proliferation and induces apoptosis and autophagy of human pharynx, tongue, and salivary gland cancer cell lines and of mouse salivary gland cancer cells (SALTO). (±)-GOS was able to: (a) decrease the ErbB2 protein expression; (b) inhibit the phosphorylation of ERK1/2 and AKT; (c) stimulate p38 and JNK1/2 protein phosphorylation. (±)-GOS administration was safe in BALB/c mice and it reduced the growth of transplanted SALTO cells in vivo and prolonged mice median survival. Our results suggest the potential role of (±)-GOS as an antitumor agent in HNC patients.

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“…Due to cases of irreversible infertility in up to 20% of men, this use was discontinued. Later on, gossypol was identified as a BH3 mimetic, a drug that can inhibit anti-apoptotic members of the BCL-2 family, and was shown to evoke cell death in multiple in vivo and in vitro models [69][70][71][72][73][74]. Gossypol can occur as two racemic enantiomers, (+)-gossypol and (−)-gossypol (also called AT-101), with AT-101 being more potent as a cancer drug.…”

Section: Pro-death Mitophagy Triggered By Gossypol/at-101mentioning

confidence: 99%

Autophagy in Cancer Cell Death

Linder

Kögel

2019

Biology

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Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment.

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AT-101 inhibits hedgehog pathway activity and cancer growth

Cited by 18 publications

References 48 publications

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

(±)-Gossypol induces apoptosis and autophagy in head and neck carcinoma cell lines and inhibits the growth of transplanted salivary gland cancer cells in BALB/c mice

Autophagy in Cancer Cell Death

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