Date of Award

2021

Document Type

Dissertation

Degree Name

Philosophy (Ph.D)

Department

Pharmaceutical Sciences

First Advisor

Blase Billack

Second Advisor

Zhe-Sheng Chen

Third Advisor

Sandra Reznik

Abstract

Colorectal cancer is the third leading cause of cancer related deaths in the United States. Currently, irinotecan, a topoisomerase I inhibitor, is an important anticancer drug approved for patients with advanced or recurrent colorectal cancer. Considering the low response rate and the events of high toxicity caused by irinotecan, we evaluated a series of thirteen thiazolyl hydrazone derivatives of 1-indanone for their potential antineoplastic activity and four compounds showed promising anticancer activity against most of the tested colon cancer cell lines with IC50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 μM. It is noteworthy that the compound, N-Indan-1-ylidene-N'-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6) is found to be more effective than irinotecan against p53 mutant colon cancer cells, HT-29, COLO 205, and KM 12 than p53 wild-type colon cancer cell line such as HCT 116. Mechanistic studies reveal that ITH-6 arrests these cancer cell lines in G2/M phase of the cell cycle, induces apoptosis, and causes an increase in ROS level with a significant reduction in the GSH level. The cell cycle arrest is related to the inhibition of tubulin polymerization in the mitotic phase. Moreover, ITH-6 inhibits the expression of NF-kB p65 and Bcl-2, which proves its cytotoxic action. The downregulation of NF-kB p65 can be further proved by immunofluorescence. Moreover, CRISPR/Cas9 was applied to establish NF-kB p65 gene knockout HT-29 cell model to validate the target of ITH-6. In addition, ITH-6 significantly decreased tumor size, growth rate and tumor volume in mice bearing HT-29 and KM 12 tumor xenografts. Overall, the results suggest that ITH-6 could be a potential anticancer drug candidate for p53 mutant colon cancers.

Download

Included in

Pharmacology Commons

Share

COinS