A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

Samadi, Abbas; Mukerji, Ridhwi; Shah, Amol; Timmermann, Barbara N.; Cohen, Mark S.

doi:10.1016/j.surg.2010.09.026

Cited by 53 publications

(40 citation statements)

References 23 publications

(24 reference statements)

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“…As such, it has demonstrated the ability to modulate many pathways involved in promoting cancer progression including specific proteins like heat shock protein (HSP) 90, Akt, NFkappaB, and the estrogen receptor (ER) [24-34]. Promising anti-tumor efficacy has been observed in prostate, thyroid, breast, melanoma, ovarian, cervical, and brain cancer models [19, 32, 35-40]. …”

Section: Introductionmentioning

confidence: 99%

Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation

et al. 2014

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Temozolomide (TMZ) has remained the chemotherapy of choice in patients with glioblastoma multiforme (GBM) primarily due to the lack of more effective drugs. Tumors, however, quickly develop resistance to this line of treatment creating a critical need for alternative approaches and strategies to resensitize the cells. Withaferin A (WA), a steroidal lactone derived from several genera of the Solanaceae plant family has previously demonstrated potent anti-cancer activity in multiple tumor models. Here, we examine the effects of WA against TMZ-resistant GBM cells as a monotherapy and in combination with TMZ. WA prevented GBM cell proliferation by dose-dependent G2/M cell cycle arrest and cell death through both intrinsic and extrinsic apoptotic pathways. This effect correlated with depletion of principle proteins of the Akt/mTOR and MAPK survival and proliferation pathways with diminished phosphorylation of Akt, mTOR, and p70 S6K but compensatory activation of ERK1/2. Depletion of tyrosine kinase cell surface receptors c-Met, EGFR, and Her2 was also observed. WA demonstrated induction of N-acetyl-L-cysteine-repressible oxidative stress as measured directly and through a subsequent heat shock response with HSP32 and HSP70 upregulation and decreased HSF1. Finally, pretreatment of TMZ-resistant GBM cells with WA was associated with O6-methylguanine-DNA methyltransferase (MGMT) depletion which potentiated TMZ-mediated MGMT degradation. Combination treatment with both WA and TMZ resulted in resensitization of MGMT-mediated TMZ-resistance but not resistance through mismatch repair mutations. These studies suggest great clinical potential for the utilization of WA in TMZ-resistant GBM as both a monotherapy and a resensitizer in combination with the standard chemotherapeutic agent TMZ.

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Section: Introductionmentioning

confidence: 99%

Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation

et al. 2014

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“…Adult T-cell leukemia/lymphoma [104] Breast cancer [64,105] Soft tissue sarcoma [106] RET protooncogene Thyroid cancer [23] Par-4 Prostate cancer [22] Mitosis Tubulin Breast cancer [78] ATP-binding site, the middle domain may interact with client proteins, and the C-terminal domain is responsible for dimerization of Hsp90. An additional ATP-binding site is also present in the C-terminus.…”

Section: Stat3mentioning

confidence: 99%

“…WFA has shown to have potent cytotoxic effects on various cancer cell types. Anticancer activity of WFA has been reported against uveal melanoma [9], glioblastoma cells [10], neuroblastoma and multiple myeloma [11], leukemia [12,13], breast [14][15][16][17], colon [18], ovarian [19], pancreatic [20], prostate [21,22], thyroid [23], and head and neck cancer cells [24].…”

Section: Introductionmentioning

confidence: 99%

Potential Anticancer Properties and Mechanisms of Action of Withanolides

Samadi

2015

The Enzymes

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“…WA (23) and RPI-1 (24) inhibit total and phospho-RET levels and activation of ERKs and AKT, whereas RPI-1 also inhibits activation of phospholipase Cγ (PLCγ) (24). It seems likely that there are no differences in the inhibitory effects of WA and RPI-1 on enteric neurogenesis.…”

Section: Underlying Mechanism For An Sr4-agonist Facilitated Neurogenmentioning

confidence: 99%

Activation of 5-HT<sub>4</sub> receptors facilitates neurogenesis of injured enteric neurons at an anastomosis in the lower gut

Takaki

Goto

Kawahara

et al. 2015

J. Smooth Muscle Res.

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Two-photon microscopy (2PM) can enable high-resolution deep imaging of thick tissue by exciting a fluorescent dye and protein at anastomotic sites in the mouse small intestine in vivo. We performed gut surgery and transplanted neural stem cells (NSC) from the embryonic central nervous system after marking them with the fluorescent cell linker, PKH26. We found that neurons differentiated from transplanted NSC (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSC (YFP [+]) could be localized within the granulation tissue of anastomoses. A 5-HT4-receptor agonist, mosapride citrate (MOS), significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P<0.005). The distribution patterns of PKH (+) neurons were similar to those of YFP (+) neurons. On the other hand, the 5-HT4-receptor antagonist, SB-207266 abolished these effects of MOS. These results indicate that neurogenesis from transplanted NSC is facilitated by activation of 5-HT4-receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than exclusive cell transplantation in treating Hirschsprung's disease and related disorders including post rectal cancer surgery. The underlying mechanisms for its action were explored using immunohistochemistry of the longitudinal mouse ileum and rat rectal preparations including an anastomosis. MOS significantly increased the number of new neurons, but not when co-administered with either of a protein tyrosine kinase receptor, c-RET two inhibitors. The c-RET signaling pathway contributes to enteric neurogenesis facilitated by MOS. In the future, we would perform functional studies of new neurons over the thick granulation tissue at anastomoses, using in vivo imaging with 2PM and double transgenic mice expressing a calcium indicator such as GCaMP6 and channelrhodopsin.

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A novel RET inhibitor with potent efficacy against medullary thyroid cancer in vivo

Cited by 53 publications

References 23 publications

Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation

Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation

Potential Anticancer Properties and Mechanisms of Action of Withanolides

Activation of 5-HT<sub>4</sub> receptors facilitates neurogenesis of injured enteric neurons at an anastomosis in the lower gut

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