Open AccessConophylline suppresses pancreatic cancer desmoplasia and cancer‐promoting cytokines produced by cancer‐associated fibroblasts
Author(s) -
Ishii Norihiro,
Araki Kenichiro,
Yokobori Takehiko,
Hagiwara Kei,
Gantumur Dorgormaa,
Yamanaka Takahiro,
Handa Tadashi,
Tsukagoshi Mariko,
Igarashi Takamichi,
Watanabe Akira,
Kubo Norio,
Harimoto Norifumi,
Masamune Atsushi,
Umezawa Kazuo,
Kuwano Hiroyuki,
Shirabe Ken
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13847
Subject(s) - desmoplasia , pancreatic cancer , cancer research , cancer , medicine , chemokine , cancer cell , stroma , gemcitabine , oncogene , pathology , immunohistochemistry , inflammation , cell cycle
Despite recent advances in cancer treatment, pancreatic cancer is a highly malignant tumor type with a dismal prognosis and it is characterized by dense desmoplasia in the cancer tissue. Cancer‐associated fibroblasts (CAF) are responsible for this fibrotic stroma and promote cancer progression. We previously reported that a novel natural compound conophylline (CnP) extracted from the leaves of a tropical plant reduced liver and pancreatic fibrosis by suppression of stellate cells. However, there have been no studies to investigate the effects of CnP on CAF, which is the aim of this work. Here, we showed that CAF stimulated indicators of pancreatic cancer malignancy, such as proliferation, invasiveness, and chemoresistance. We also showed that CnP suppressed CAF activity and proliferation, and inhibited the stimulating effects of CAF on pancreatic cancer cells. Moreover, CnP strongly decreased the various cytokines involved in cancer progression, such as interleukin (IL)‐6, IL‐8, C‐C motif chemokine ligand 2 (CCL2), and C‐X‐C motif chemokine ligand 12 (CXCL12), secreted by CAF. In vivo, CAF promoted tumor proliferation and desmoplastic formation in a mouse xenograft model, CnP reduced desmoplasia of tumors composed of pancreatic cancer cells + CAF, and combination therapy of CnP with gemcitabine remarkably inhibited tumor proliferation. Our findings suggest that CnP is a promising therapeutic strategy of combination therapy with anticancer drugs to overcome refractory pancreatic cancers.