homocamptothecin and Lung-Neoplasms

Arl4c is overexpressed in several cancer tissues and is involved in cancer development. Nevertheless, the exact mechanism that regulates Arl4c expression in lung cancer has not been fully elucidated. The aim of this study was to investigate the regulatory mechanism of Arl4c and to explore potential chemotherapeutic drugs targeting Arl4c.. Immunohistochemistry was used to examine Arl4c expression levels in human lung adenocarcinoma cancer specimens. Protein expression was detected by western blot. Overexpression of Arl4c-Flag protein was used to detect the ubiquitination of Arl4c. A short interfering RNA against Arl4c was used for gene silencing.. Arl4c was overexpressed in lung cancer tissues, and knockdown of Arl4c expression by siRNA decreased lung cancer A549 and 95-D cell proliferation. In addition, Arl4c expression was downregulated via inhibition of the AKT pathway in A549 and 95-D cells, whereas exposure to benzo (a) pyrene (a carcinogen in smoke) increased Arl4c expression in 16HBE cells via AKT activation. Finally, we found that chemotherapy drug hydroxycamptothecin (HCPT) could decrease Arl4c expression levels by inhibiting the activation of the AKT pathway in A549 and 95-D cells. Moreover, accumulation of ubiquitinated Arl4c protein was increased by HCPT and LY294002 (an AKT inhibitor) treatment whereas the proteasome inhibitor MG-132 attenuated the inhibitory effect of HCPT and LY294002 on Arl4c expression.. Here, we highlighted the AKT pathway as an important regulatory pathway for Arl4c expression in lung cancer cells and identified HCPT as a promising drug for lung adenocarcinoma treatment that functioned by targeting Arl4c expression.

Topics: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung; ADP-Ribosylation Factors; Blotting, Western; Camptothecin; Cell Line, Tumor; Chromones; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Leupeptins; Lung Neoplasms; Morpholines; Proto-Oncogene Proteins c-akt; Signal Transduction; Smoking

In an effort to improve the stability of homocamptothecin and reduce the toxicity, novel homocamptothecin analogs with acylamino groups at C(9) were designed and synthesized. The cytotoxic activities of all the synthetic compounds against three cancer cell lines were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and irinotecan was used as reference compound. Compound 7c with a piperidinylacetamido group and 10a with phenylacetamido group at C(9) showed potent activities both in vitro and in vivo. In addition, they also revealed remarkable topoisomerase I inhibitions which were exhibited with well-established bonds with amino acid residues Arg364 and Asp533 in the active pocket. On the basis of the biological activities, 7c and 10a would be potential candidates for further studies.

Topics: Animals; Apoptosis; Binding Sites; Camptothecin; Catalytic Domain; Cell Line, Tumor; DNA Cleavage; DNA Topoisomerases, Type I; Enzyme Activation; HCT116 Cells; Humans; Lung Neoplasms; Mice; Mice, Nude; Molecular Docking Simulation; Structure-Activity Relationship; Topoisomerase I Inhibitors; Transplantation, Heterologous