title: Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform.
abstract: Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holds promise for optimization of anti-cancer combination chemotherapy.
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China, and Department of Anatomy and Cell Biology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Deng
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Daming
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China, and Department of Anatomy and Cell Biology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, The Forth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
authors.forename: Wanhai
authors.initials: W
authors.lastname: Xu
authors.affiliation: Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lv
authors.affiliation: Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: He
authors.affiliation: School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China, and Department of Anatomy and Cell Biology, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Therapeutics McGill University Medical School 3655 Sir William Osler Promenade #1309, Montreal, Quebec Canada.
authors.forename: Moshe
authors.initials: M
authors.lastname: Szyf
authors.affiliation: Mechanical and Aerospace Engineering Department, Biomedical Engineering Department, University of California, Los Angeles, CA 90095-1597, USA.
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Ho
authors.affiliation: 1] Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China [2] Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China.
authors.forename: Jingde
authors.initials: J
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D006801:Humans; D051379:Mice; D008962:Models, Theoretical; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents