title: The chemopreventive and clinically used agent curcumin sensitizes HPV (-) but not HPV (+) HNSCC to ionizing radiation, in vitro and in a mouse orthotopic model.
abstract: Radiation therapy (RT) plays a critical role in the local-regional control of head and neck squamous cell carcinoma (HNSCC). However, the efficacy of RT in treating HNSCC is limited by severe normal tissue toxicity, predominantly mucositis. One pharmacological approach for increasing the clinical response to RT is the use of radiation response modifiers that preferentially sensitize tumor cells. Previously we demonstrated that curcumin, a natural plant polyphenol, increased the radiation sensitivity of HNSCC cells and that the observed sensitization was dependent on curcumin-mediated inhibition of thioredoxin reductase 1 (TxnRd1) a key cytosolic regulator of redox-dependent signaling. Here, we examined curcumin-induced radiation sensitization in HNSCC cell lines with differing HPV status and expressing different levels of TxnRd1, in vitro. The intrinsic radiation resistance of the HPV (-) cell lines was significantly higher than the HPV (+) cell lines used in our study. Notably, all of the HPV (-) cell lines expressed high levels of TxnRd1 and exhibited higher intrinsic resistance to RT. While curcumin was effective at increasing the radiation response of the resistant HPV (-) cell lines it had no effect on the HPV (+) cells. Based on these findings we employed an orthotopic, HPV (-) HNSCC tumor model in athymic nude mice to examine the effect of combining curcumin with fractionated RT, in vivo. The combination of curcumin feeding and fractionated RT had a significant effect on tumor doubling time and overall animal survival. We therefore propose that curcumin and RT should be considered as a first line treatment of HPV (-) HNSCC.
authors.affiliation: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tuttle
authors.forename: Lauren
authors.initials: L
authors.lastname: Hertan
authors.forename: Natalie
authors.initials: N
authors.lastname: Daurio
authors.forename: Sarah
authors.initials: S
authors.lastname: Porter
authors.forename: Charanya
authors.initials: C
authors.lastname: Kaushick
authors.forename: Daqing
authors.initials: D
authors.lastname: Li
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Myamoto
authors.forename: Alex
authors.initials: A
authors.lastname: Lin
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy / Q000821:virology*; D045744:Cell Line, Tumor; D018890:Chemoprevention; D003474:Curcumin / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy / Q000821:virology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D027383:Papillomaviridae / Q000235:genetics*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology*; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D054481:Thioredoxin Reductase 1; D003474:Curcumin