Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer

• Published in: Cancer letters 2017-06, Vol.396, p.155-166
• Main Authors: Jung, Kyung Hee, Choi, Il-Kyu, Lee, Hee-Seung, Yan, Hong Hua, Son, Mi Kwon, Ahn, Hyo Min, Hong, JinWoo, Yun, Chae-Ok, Hong, Soon-Sun
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adenovirus; Adenoviruses; Animals; Antimetabolites, Antineoplastic - pharmacology; Antitumor activity; Apoptosis; Cancer therapies; Chemoresistance; Chemotherapy; Collagen; Combined Modality Therapy; Combined treatment; Cytotoxicity; Degradation; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Elastin; Extracellular matrix; Fibronectin; Gemcitabine; HEK293 Cells; Hematology, Oncology and Palliative Medicine; Humans; Male; Mice; Mice, Nude; Oncolysis; Oncolytic Virotherapy - methods; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; Pancreatic Neoplasms - virology; Random Allocation; Relaxin; Relaxin - biosynthesis; Relaxin - genetics; Rodents; Spheroids; Tumors; Viruses; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.03.009

Abstract Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1–50 μM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01–0.05 μM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis.