title: Quinacrine synergizes with 5-fluorouracil and other therapies in colorectal cancer.
abstract: Although treatments have improved patient prognosis in surgically resectable colorectal cancer, new effective drugs with improved safety profiles are needed to improve the currently poor outcomes of patients with recurrent or metastatic colorectal cancer. Quinacrine, a small molecule anti-malarial agent that has activity in giardiasis, lupus, prion disease, and used as a means of non-surgical sterilization, has shown cytotoxic activity across a broad range of cancers. Here, we evaluate the potential of adding quinacrine to anticancer chemotherapeutics and targeted agents as a potential novel combinatorial therapy for advanced colon cancer. We show that quinacrine synergizes with 5-fluorouracil and significantly enhances the cytotoxicity of sorafenib in a panel of 10 human colorectal cancer cell lines, including those with KRAS mutations protein gel blot analysis confirmed that quinacrine's anticancer activity partially arises from its ability to stabilize p53 and lower anti-apoptotic protein levels. In a series of in vivo studies, quinacrine monotherapy lowered the tumor load of nu/nu mice bearing human colorectal cancer xenografts. In combination, quinacrine and 5-Fluorouracil significantly delayed tumor growth of a variety of different xenografts, as compared to each agent administered alone. Our results suggest that the administration of quinacrine in combination with chemotherapeutic agents and targeted agents should be further explored in patients with recurrent, locally advanced, or metastatic colorectal cancer.
authors: Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Hematology/Oncology Division, Penn State Hershey Cancer Institute, Penn State Hershey Medical Center, Hershey, PA, USA.
authors: Jean-Nicolas
authors: JN
authors: Gallant
authors: Joshua E
authors: JE
authors: Allen
authors: Charles D
authors: CD
authors: Smith
authors: David T
authors: DT
authors: Dicker
authors: Wenge
authors: W
authors: Wang
authors: Nathan G
authors: NG
authors: Dolloff
authors: Arunasalam
authors: A
authors: Navaraj
authors: Wafik S
authors: WS
authors: El-Deiry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines / Q000494:pharmacology; D011796:Quinacrine / Q000008:administration & dosage / Q000494:pharmacology*; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; C117307:KRAS protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077157:Sorafenib; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D011796:Quinacrine; D005472:Fluorouracil