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.
journal_name
Cancer Lettjournal_title
Cancer lettersauthors
Jung KH,Choi IK,Lee HS,Yan HH,Son MK,Ahn HM,Hong J,Yun CO,Hong SSdoi
10.1016/j.canlet.2017.03.009subject
Has Abstractpub_date
2017-06-28 00:00:00pages
155-166eissn
0304-3835issn
1872-7980pii
S0304-3835(17)30173-8journal_volume
396pub_type
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