Sulforaphane enhances irradiation effects in terms of perturbed cell cycle progression and increased DNA damage in pancreatic cancer cells

Patrick Naumann,Jakob Liermann,Thomas E Schmid,Jürgen Debus,Klaus-Josef Weber,Franco Fortunato,Stephanie E Combs,Aamir Ahmad

doi:10.1371/journal.pone.0180940

Abstract

BackgroundSulforaphane (SFN), an herbal isothiocyanate enriched in cruciferous vegetables like broccoli and cauliflower, has gained popularity for its antitumor effects in cell lines such as pancreatic cancer. Antiproliferative as well as radiosensitizing properties were reported for head and neck cancer but little is known about its effects in pancreatic cancer cells in combination with irradiation (RT).MethodsIn four established pancreatic cancer cell lines we investigated clonogenic survival, analyzed cell cycle distribution and compared DNA damage via flow cytometry and western blot after treatment with SFN and RT.ResultsBoth SFN and RT show a strong and dose dependent survival reduction in clonogenic assays, an induction of a G2/M cell cycle arrest and an increase in γH2AX protein level indicating DNA damage. Effects were more pronounced in combined treatment and both cell cycle perturbation and DNA damage persisted for a longer period than after SFN or RT alone. Moreover, SFN induced a loss of DNA repair proteins Ku 70, Ku 80 and XRCC4.ConclusionOur results suggest that combination of SFN and RT exerts a more distinct DNA damage and growth inhibition than each treatment alone. SFN seems to be a viable option to improve treatment efficacy of chemoradiation with hopefully higher rates of secondary resectability after neoadjuvant treatment for pancreatic cancer.

Highlights

Despite its low incidence pancreatic cancer is still the fourth leading cause of cancer death
Effects were more pronounced in combined treatment and both cell cycle perturbation and DNA damage persisted for a longer period than after SFN or RT alone
Our results suggest that combination of SFN and RT exerts a more distinct DNA damage and growth inhibition than each treatment alone

Summary

Introduction

Despite its low incidence pancreatic cancer is still the fourth leading cause of cancer death. While progress and innovation in oncology managed to improve 5-year survival rates of all tumor entities by approximately 20%, advances have been slow for pancreatic cancer [1]. Main reasons are lack of early symptoms with subsequent late diagnosis mostly at advanced or even metastasized stages as well as a relative resistance to chemotherapeutics and irradiation (RT) [2]. At time of diagnosis less than one fourth of all patients have a disease that is amenable to surgical resection. In locally advanced stage, which comprises none metastasized but due to vessel involvement inoperable tumors, neoadjuvant chemoradiation is a reasonable treatment choice to potentially reach secondary resectability that improves survival rates significantly [3, 5, 6]. Antiproliferative as well as radiosensitizing properties were reported for head and neck cancer but little is known about its effects in pancreatic cancer cells in combination with irradiation (RT)

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Results

Conclusion