Tania Pilli1, Silvia Cantara1, Carlotta Marzocchi1, Furio Pacini1, Bellur S Prabhakar2, Maria Grazia Castagna3. 1. Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy. 2. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA. 3. Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy. m.g.castagna@ao-siena.toscana.it.
Abstract
PURPOSE: Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206). METHODS: Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C). RESULTS: C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model. CONCLUSIONS: TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
PURPOSE:Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206). METHODS: Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C). RESULTS: C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model. CONCLUSIONS:TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
Authors: H Walczak; R E Miller; K Ariail; B Gliniak; T S Griffith; M Kubin; W Chin; J Jones; A Woodward; T Le; C Smith; P Smolak; R G Goodwin; C T Rauch; J C Schuh; D H Lynch Journal: Nat Med Date: 1999-02 Impact factor: 53.440
Authors: David M Hyman; Igor Puzanov; Vivek Subbiah; Jason E Faris; Ian Chau; Jean-Yves Blay; Jürgen Wolf; Noopur S Raje; Eli L Diamond; Antoine Hollebecque; Radj Gervais; Maria Elena Elez-Fernandez; Antoine Italiano; Ralf-Dieter Hofheinz; Manuel Hidalgo; Emily Chan; Martin Schuler; Susan Frances Lasserre; Martina Makrutzki; Florin Sirzen; Maria Luisa Veronese; Josep Tabernero; José Baselga Journal: N Engl J Med Date: 2015-08-20 Impact factor: 91.245
Authors: Madhu Ramaswamy; Elena V Efimova; Osvaldo Martinez; Nirupama U Mulherkar; Surya P Singh; Bellur S Prabhakar Journal: Oncogene Date: 2004-08-12 Impact factor: 9.867
Authors: V Gunda; O Bucur; J Varnau; P Vanden Borre; M J Bernasconi; R Khosravi-Far; S Parangi Journal: Cell Death Dis Date: 2014-03-06 Impact factor: 8.469
Authors: Kaihua Zhong; Dong Chen; Zhiming Wu; Xiaohong Wang; Bin Pan; Nanhui Chen; Weifeng Zhong Journal: Nan Fang Yi Ke Da Xue Xue Bao Date: 2020-11-30