Anticancer effect of Indanone-based thiazolyl hydrazone derivative on p53 mutant colorectal cancer cell lines: An in vitro and in vivo study

Abstract

Colorectal cancer is a major health problem, and it is the third most diagnosed cancer in the United States. The current treatment for colorectal cancer includes irinotecan, a topoisomerase I inhibitor, and other targeted drugs, such as bevacizumab and regorafenib. The low response rates and incidence of high toxicity caused by these drugs instigated an evaluation of the anticancer efficacy of a series of 13 thiazolyl hydrazone derivatives of 1-indanone, and four compounds among them show favorable anticancer activity against some of the tested colorectal cancer cell lines with IC50 values ranging from 0.41 ± 0.19 to 6.85 ± 1.44 μM. It is noteworthy that one of the indanone-based thiazolyl hydrazone (ITH) derivatives, N-Indan-1-ylidene-N’-(4-Biphenyl-4-yl-thiazol-2-yl)-hydrazine (ITH-6), has a better cytotoxicity profile against p53 mutant colorectal cancer cells HT-29, COLO 205, and KM 12 than a p53 wild-type colorectal cancer cell line, such as HCT 116. Mechanistic studies show that ITH-6 arrests these three cancer cell lines in the G2/M phase and induces apoptosis. It also causes a rise in the reactive oxygen species level with a remarkable decrease in the glutathione (GSH) level. Moreover, ITH-6 inhibits the expression of NF-κB p65 and Bcl-2, which proves its cytotoxic action. In addition, ITH-6 significantly decreased tumor size, growth rate, and tumor volume in mice bearing HT-29 and KM 12 tumor xenografts. Moreover, CRISPR/Cas9 was applied to establish an NF-κB p65 gene knockout HT-29 cell line model to validate the target of ITH-6. Overall, the results suggest that ITH-6 could be a potential anticancer drug candidate for p53 mutant colorectal cancers.

Chemical Derivatization Leads to the Discovery Of Novel Analogs of Azotochelin, a Natural Siderophore, as Promising Anticancer Agents

“…A synthetic strategy was developed to diversify the azotochelin structure and generate an extensive library of analogs for biological evaluation. The research synthesized a methyl ester analog of azotochelin ( 14), substituted benzyla- mides of azotochelin (28)(29)(30)(31)(32)(33)(34), substituted phenethylamides of azotochelin (35)(36)(37)(38)(39)(40), and aromatic modified analogs of azotochelin (52-54). These efforts thoroughly evaluated the structureactivity relationship of different functionalities within the azotochelin scaffold.…”

“…Dulbecco's modified ‐eagle medium (DMEM) was used for the cell culture supplemented with 10 % fetal bovine serum (FBS) and 1 % penicillin‐streptomycin (PS) at 37 °C in a humidified atmosphere of 5 % CO 2 . Cells were grown for two weeks in monolayers (except K‐562, which grows in suspended clusters) before the start of any experiment [34–37] …”

“…For the NCIÀ H460 cell line, all tested compounds showed potency with sub-micromolar IC 50 values (Table 4), indicating that various functional groups are tolerated at this position. Overall, it can be stated that the amidation of azotochelin with substituted phenylethylamines (35)(36)(37)(38)(39)(40) improved the cytotoxicity in NCIÀ H460 and, in some cases, against SNB-19 cell lines. All the analogs, except compound 39, exhibited selectivity towards cancer cell lines.…”

“…Cells were grown for two weeks in monolayers (except K-562, which grows in suspended clusters) before the start of any experiment. [34][35][36][37]…”