title: Antitumor activity of semisynthetic derivatives of Aconitum alkaloids.
abstract: We recently synthesized from aconitine a series of drugs with in vitro and in vivo antitumor properties, among which bis[O-(14-benzoylaconine-8-yl)]suberate (BBAS) was the most active (Eur J Med Chem 2012; 54: 343). In the present work, we used the NCI panel of 60 human tumor cell lines to identify the most sensitive cell lines and drugs with comparable cytotoxicity profiles. GI50 values of BBAS ranged between 0.12 and 6.5 μM. Activity was higher than average for leukemia and melanoma cell lines, especially SK-MEL-5 and SK-MEL-28, for the COLO-205 and HT-29 (colorectal) and MDA-MB-468 (breast) cancer cell lines. We evaluated the correlation between the GI50 of BBAS and those of 125 antiproliferative compounds with various mechanisms of action, using Bonferroni correction for multiple testing, and we observed a highly significant correlation with the GI50s of nitrosoureas. Interestingly, BBAS cytotoxicity was inversely correlated with the expression levels of MGMT (p = 0.009), an enzyme involved in the repair of nitrosourea-induced DNA damage. However, no correlation was found with the expression of 102 other genes involved in DNA repair. Antitumor activity was tested on immunodeficient mice with subcutaneously xenografted COLO-205, HT-29, MDA-MB-468, SK-MEL-5 and SK-MEL-28 cell lines. At 10 mg/kg, there was a significant reduction in tumor size with T/C values of 41 % and 43 % for COLO-205 and SK-MEL-28 cell lines, respectively. The drug was less active on HT-29 and SK-MEL-5 and inactive on MDA-MB-468 xenografts. Cell cycle studies showed an accumulation of BBAS-treated cells in G2/M phase after treatment at 20 μM. Together, our results allowed the identification of a potentially new class of anticancer agent displaying a mechanism of action related to that of nitrosoureas.
authors.affiliation: Institut Bergonié, INSERM U916, Université Bordeaux Segalen, 229 cours de l'Argonne, 33076, Bordeaux, France.
authors.forename: Ainura
authors.initials: A
authors.lastname: Chodoeva
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Bosc
authors.forename: Lydia
authors.initials: L
authors.lastname: Lartigue
authors.forename: Jean
authors.initials: J
authors.lastname: Guillon
authors.forename: Céline
authors.initials: C
authors.lastname: Auzanneau
authors.forename: Pierre
authors.initials: P
authors.lastname: Costet
authors.forename: Ashiraly
authors.initials: A
authors.lastname: Zurdinov
authors.forename: Christian
authors.initials: C
authors.lastname: Jarry
authors.forename: Jacques
authors.initials: J
authors.lastname: Robert
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D031841:Aconitum / Q000737:chemistry*; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice
chemical_list: D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; C047307:benzoylaconine; D000157:Aconitine