TITLE: Therapeutic repurposing of benserazide for colon cancer ABSTRACT: We have recently identified cystathionine-beta-synthase (CBS)-derived hydrogen sulfide (H2S) as an endogenous tumor-promoting factor and thus a potential new therapeutic target in colorectal cancer. The importance of CBS-derived H2S in the pathobiology of colorectal cancer is supported by: 1) the significant anti- tumorigenic effects of CBS gene silencing, and 2) induction of an invasive metastatic phenotype when aberrantly overexpressed. Also, treatment with the prototypical CBS inhibitor aminooxyacetic acid (AOAA) reduces colon cancer cell proliferation in vitro and tumor growth and metastasis in vivo. However, the potency, specificity and selectivity of AOAA is suboptimal. Moreover, no clinically used, professional CBS inhibitors exist. To facilitate the translation of CBS inhibitors as anticancer therapeutics, via the repurposing route, we have conducted a virtual screening 260,000 compounds, with special emphasis of (a) commonalities in the emerging structures and (b) potential availability of the identified compounds for rapid repurposing. The virtual screening was conducted using a combination of publicly available software. The results produced several common scaffolds, one of them being a class of compounds which also included benserazide, a clinically used anti- Parkinson compound with its original pharmacological action of being a peripherally acting DOPA decarboxylase inhibitor. We have tested benserazide in vitro on human recombinant CBS, and confirmed it CBS inhibitory activity. In order to begin clinical translation of the compounds into the direction of anticancer effects, we have also tested its effect in HCT116 cells, a human colon cancer line. The compound caused a concentration-dependent inhibition of HCT116 proliferation. We have also conducted Pubmed searches and have compared the antiproliferative concentration range of benserazide with the concentration range of the compound in patients; have done pharmacokinetic/pharmacodynamic modeling using publicly available software (Winnonlin) to estimate the concentrations of benserazide likely achievable in the tumor tissue of patients. Taken together, these data suggest that benserazide, after an appropriately selected set of preclinical studies proposed in the current application, may be a candidate for repurposing for the clinical therapy of colon cancer.
Aim 1 will focus on hit validation and repurposing feasibility testing in vitro.
Aim 2 will focus on ?hit? validation in vivo. Completion of the proposed project is expected to demonstrate the efficacy of benserazide as an anticancer agent, and is expected to build preclinical rationale for the repurposing of benserazide for the experimental therapy of patients with advanced colorectal cancer. The applicant team has all necessary theoretical and practical expertise to conduct the proposed work.

Public Health Relevance

Hydrogen sulfide (H2S) (commonly known as 'swamp gas' or 'sewer gas') has been recently identified as a biological substance produced in colon cancer cells by a protein called CBS which, if blocked, causes cancer cells t o lose their 'fuel supply' and stop growing. This project aims to test the feasibility that benserazide, a clinically used anti-Parkinson compound, may be suitable for repurposing for the experimental therapy of cancer, because it has an additional pharmacological action as a CBS inhibitor thereby blocking H2S synthesis of tumor cells. We propose to evaluate this compound in cell- based models, biochemical assays and in colon cancer animal models.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21TR001734-01
Application #
9205447
Study Section
Special Emphasis Panel (ZTR1-DPI-2 (01))
Program Officer
Austin, Bobbie Ann
Project Start
2016-09-28
Project End
2018-08-31
Budget Start
2016-09-28
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$271,250
Indirect Cost
$96,250
Name
University of Texas Medical Br Galveston
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Untereiner, Ashley A; Pavlidou, Athanasia; Druzhyna, Nadiya et al. (2018) Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells. Biochem Pharmacol 149:174-185