Timosaponin AIII Is Preferentially Cytotoxic to Tumor Cells through Inhibition of mTOR and Induction of ER Stress

King, Frank W.; Fong, Sylvia; Griffin, Chandi; Shoemaker, Mark; Staub, Rick; Zhang, Yanling; Cohen, Isaac; Shtivelman, Emma

doi:10.1371/journal.pone.0007283

Cited by 71 publications

(71 citation statements)

References 42 publications

(58 reference statements)

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“…Timosaponin AIII selectively induces cell death in BT474 and MDAM231 breast carcinoma cells, but not in normal MCF10A immortalized mammary epithelial cells. It exerts its anti-proliferative activity by inhibiting phosphorylation of Akt and mTOR, as well as p70S6K and 4E-BP1 (King et al, 2009). This compound is still in pre-clinical stages and has not progressed into clinical trials.…”

Section: Natural Phytochemicals As Mtor Inhibitorsmentioning

confidence: 99%

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

Tan¹,

Moad²,

Tan³

2014

Asian Pacific Journal of Cancer Prevention

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The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.

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Section: Natural Phytochemicals As Mtor Inhibitorsmentioning

confidence: 99%

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

Tan¹,

Moad²,

Tan³

2014

Asian Pacific Journal of Cancer Prevention

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“…Apoptotic cells were evaluated in vitro by Annexin V/ propidium iodide staining (Invitrogen) according to the manufacturer's instructions, as previously described (19). Cells were analyzed via flow cytometry.…”

Section: Assessment Of Apoptosis In Vitro and In Vivomentioning

confidence: 99%

Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin via Reactive Oxygen Species Modulation

Ding

Hui

Shi

et al. 2011

Clinical Cancer Research

161

102

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Purpose: Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC.Experimental Design: Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis.Results: Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy-specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy.Conclusions: Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients.

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“…(9,10) Recently, timosaponin AIII was also shown to be preferentially toxic to breast cancer cell lines over non-transformed cells. (11) Therefore, we assessed the effects of timosaponin AIII on the migration potential of melanoma cells using in vitro assays and an in vivo metastasis model in mice, in which timosaponin AIII had not previously been evaluated. In this study, we assessed the chemotherapeutic effects of timosaponin AIII by evaluating melanoma cell migration, because tumor cell migration is a major event in the metastatic cascade.…”

mentioning

confidence: 99%

Timosaponin AIII inhibits melanoma cell migration by suppressing COX‐2 and in vivo tumor metastasis

Kim

et al. 2016

Cancer Science

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Melanoma is the leading cause of death from skin disease, due in large part to its propensity to metastasize. We examined the effects of timosaponin AIII, a compound isolated from Anemarrhena asphodeloides Bunge, on melanoma cancer cell migration and the molecular mechanisms underlying these effects using B16-F10 and WM-115 melanoma cells lines. Overexpression of COX-2, its metabolite prostaglandin E 2 (PGE 2 ), and PGE 2 receptors (EP2 and EP4) promoted cell migration in vitro. Exposure to timosaponin AIII resulted in concentration-dependent inhibition of cell migration, which was associated with reduced levels of COX-2, PGE 2 , and PGE 2 receptors. Transient transfection of COX-2 siRNA also inhibited cell migration. Exposure to 12-O-tetradecanoylphorbal-13-acetate enhanced cell migration, whereas timosaponin AIII inhibited 12-O-tetradecanoylphorbal-13-acetate-induced cell migration and reduced basal levels of EP2 and EP4. Moreover, timosaponin AIII inhibited activation of nuclear factor-kappa B (NF-jB), an upstream regulator of COX-2 in B16-F10 cells. Consistent with our in vitro findings, in vivo studies showed that timosaponin AIII treatment significantly reduced the total number of metastatic nodules in the mouse lung and improved histological alterations in B16-F10-injected C57BL ⁄ 6 mice. In addition, C57BL ⁄ 6 mice treated with timosaponin AIII showed reduced expression of COX-2 and NF-jB in the lung. Together, these results indicate that timosaponin AIII has the capacity to inhibit melanoma cell migration, an essential step in the process of metastasis, by inhibiting expression of COX-2, NF-jB, PGE 2, and PGE 2 receptors. M elanoma is the most deadly type of skin cancer, accounting for approximately 80% of deaths caused by skin cancer.(1) Melanoma is particularly deadly due to its propensity to metastasize; clinical trials indicate that melanoma shows preferential metastasis to the lung, brain, liver, and skin. Moreover, melanoma is highly resistant to conventional chemotherapeutics.(2) Given the rising incidence of melanoma and the lack of effective therapies, development of new chemicals targeting the complex genetic networks involved in melanoma metastasis should provide new treatment strategies for this devastating disease. (3,4) Two COX isoforms with distinct physiologic functions have been identified: COX-1 and COX-2. COX-1 is expressed constitutively in many tissues and has an important role in the maintenance of homeostasis. In contrast, COX-2 is an inducible enzyme that is activated by extracellular stimuli, such as UV radiation. Enhanced expression of COX-2 in skin exposed to UV radiation has been identified as a risk factor for the development of skin cancer. (5,6) Cyclooxygenase-2 generates prostaglandins that are thought to play a central role in orchestrating the events involved in cancer invasion and metastasis. Prostaglandin E 2 (PGE 2 ) exerts its effects through G-protein coupled receptors (EP1, EP2, EP3, and EP4) and has been implicated in angiogenesis, invasion, and metastasis. (7,8)...

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Timosaponin AIII Is Preferentially Cytotoxic to Tumor Cells through Inhibition of mTOR and Induction of ER Stress

Cited by 71 publications

References 42 publications

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

The mTOR Signalling Pathway in Cancer and the Potential mTOR Inhibitory Activities of Natural Phytochemicals

Autophagy Activation in Hepatocellular Carcinoma Contributes to the Tolerance of Oxaliplatin via Reactive Oxygen Species Modulation

Timosaponin AIII inhibits melanoma cell migration by suppressing COX‐2 and in vivo tumor metastasis

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