Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer

Hideya Onishi, Yoshihiro Morifuji, Masaya Kai, Kumi Suyama, Hironori Iwasaki, Mitsuo Katano

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Abstract

Pancreatic cancer is one of the deadliest types of cancer. Previously, we showed that hypoxia increases invasiveness through upregulation of Smoothened (Smo) transcription in pancreatic ductal adenocarcinoma (PDAC) cells. Here, we first evaluated whether hypoxia-induced increase in Smo contributes to the proliferation of PDAC cells. We showed that Smo, but not Gli1, inhibition decreases proliferation significantly under hypoxic conditions. To further investigate the effects of Smo on PDAC growth, cell cycle analysis was carried out. Inhibition of Smo under hypoxia led to G0/G1 arrest and decreased S phase. As 5-fluorouracil (5-FU) and gemcitabine, which are first-line drugs for pancreatic cancer, are sensitive to S phase, we then evaluated whether cyclopamine-induced decreased S phase under hypoxia affected the chemosensitivity of 5-FU and gemcitabine in PDAC cells. Cyclopamine treatment under hypoxia significantly decreased chemosensitivity to 5-FU and gemcitabine under hypoxia in both in vitro and in vivo models. In contrast, cis-diamminedichloroplatinum, which is cell cycle-independent, showed significant synergistic effects. These results suggest that hypoxia-induced increase of Smo directly contributes to the proliferation of PDAC cells through a hedgehog/Gli1-independent pathway, and that decreased S phase due to the use of Smo inhibitor under hypoxia leads to chemoresistance in S phase-sensitive anticancer drugs. Our results could be very important clinically because a clinical trial using Smo inhibitors and chemotherapy drugs will begin in the near future.

Original languageEnglish
Pages (from-to)1272-1279
Number of pages8
JournalCancer Science
Volume103
Issue number7
DOIs
Publication statusPublished - Jul 1 2012

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gemcitabine
Pancreatic Neoplasms
Fluorouracil
S Phase
Adenocarcinoma
Cell Cycle
Pharmaceutical Preparations
Hypoxia
Cisplatin

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer. / Onishi, Hideya; Morifuji, Yoshihiro; Kai, Masaya; Suyama, Kumi; Iwasaki, Hironori; Katano, Mitsuo.

In: Cancer Science, Vol. 103, No. 7, 01.07.2012, p. 1272-1279.

Research output: Contribution to journalArticle

Onishi, Hideya ; Morifuji, Yoshihiro ; Kai, Masaya ; Suyama, Kumi ; Iwasaki, Hironori ; Katano, Mitsuo. / Hedgehog inhibitor decreases chemosensitivity to 5-fluorouracil and gemcitabine under hypoxic conditions in pancreatic cancer. In: Cancer Science. 2012 ; Vol. 103, No. 7. pp. 1272-1279.
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