Τίτλος:
Azasteroid alkylators as dual inhibitors of akt and erk signaling for the treatment of ovarian carcinoma
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
(1) Background: Previous findings show that lactam steroidal alkylating esters display improved therapeutic efficacy with reduced toxicity. The aim of this study was to evaluate the anticancer activity of two newly synthesized aza-steroid alkylators (ENGA-L06E and ENGA-L08E) against human ovarian carcinoma cells, and consequently, the dual inhibition of RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways, both of which are closely associated with ovarian cancer; (2) Methods: The in vitro cytostatic and cytotoxic effects of ENGA-L06E and ENGA-L08E were evaluated in a panel of five human ovarian cancer cell lines, as well as in in vivo studies. ENGA-L06E and ENGA-L08E, in addition to another two aniline-mustard alkylators, POPAM and melphalan (L-PAM), were utilized in order to determine the acute toxicity and antitumor efficacy on two human ovarian xenograft models. Also, in silico studies were performed in order to investigate the dual inhibition of ENGA-L06E and ENGA-L08E on RAS/PI3K/AKT and RAS/RAF/MEK/ERK signaling pathways; (3) Results: Both, in vitro and in vivo studies demonstrated that ENGA-L06E and ENGA-L08E were significantly more effective with a lower toxicity profile in comparison to POPAM and L-PAM alkylators. Moreover, in silico studies demonstrated that the two new aza-steroid alkylators could act as efficient inhibitors of the phosphorylation of AKT and ERK1/2 molecules; and (4) Conclusions: Both ENGA-L06E and ENGA-L08E demonstrated high anticancer activity through the inhibition of the PI3K-AKT and KRAS-ERK signaling pathways against human ovarian carcinoma, and thus constituting strong evidence towards further clinical development. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Dalezis, P.
Geromichalou, E.
Polonifi, A.
Sagredou, S.
Nikoleousakos, N.
Nikolaou, M.
Sarli, V.
Panayiotidis, M.I.
Trafalis, D.T.
Λέξεις-κλειδιά:
12a methyl 2 oxo 1,2,3,4,4a,4b,5,6,10b,11,12,12a dodecahydronaphtho[2,1 f]quinolin 8 yl 3 [4 [bis(2 chloroethyl)amino]phenoxy]propanoate; 4 bis(2 chloroethyl)aminophenoxypropionic acid; alkylating agent; azasteroid; enga l 06e; enga l 08e; K ras protein; melphalan; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase kinase; naphtho[1,2 d]azepin 8 yl 3 [4 [bis(2 chloroethyl)amino]phenoxy]propanoate; phosphatidylinositol 3 kinase; protein kinase B; Raf protein; Ras protein; unclassified drug, acute toxicity; Akt signaling; animal experiment; animal model; animal tissue; antineoplastic activity; Article; cancer inhibition; cell viability; computer model; controlled study; cytostasis; drug cytotoxicity; drug efficacy; drug potency; drug structure; enzyme phosphorylation; female; GI50; human; human cell; IC50; in vitro study; in vivo study; LD10; LD50; male; MAPK signaling; mouse; nonhuman; ovary carcinoma; OVCAR-3 cell line; OVCAR-5 cell line; SK-OV-3 cell line; tumor xenograft; UWB1.289 cell line
DOI:
10.3390/cancers12051263
