Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma
(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 ca...
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| Format: | Article |
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MDPI AG
2020-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/5/1263 |
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| author | Panagiotis Dalezis Eleni Geromichalou Aikaterini Polonifi Sofia Sagredou Nikolaos Nikoleousakos Michael Nikolaou Vasiliki Sarli Mihalis I. Panayiotidis Dimitrios T. Trafalis |
| author_facet | Panagiotis Dalezis Eleni Geromichalou Aikaterini Polonifi Sofia Sagredou Nikolaos Nikoleousakos Michael Nikolaou Vasiliki Sarli Mihalis I. Panayiotidis Dimitrios T. Trafalis |
| author_sort | Panagiotis Dalezis |
| collection | DOAJ |
| description | (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. |
| first_indexed | 2024-03-10T19:46:30Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T19:46:30Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-448baba0b65f4debb8d6b163c327314a2023-11-20T00:43:29ZengMDPI AGCancers2072-66942020-05-01125126310.3390/cancers12051263Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian CarcinomaPanagiotis Dalezis0Eleni Geromichalou1Aikaterini Polonifi2Sofia Sagredou3Nikolaos Nikoleousakos4Michael Nikolaou5Vasiliki Sarli6Mihalis I. Panayiotidis7Dimitrios T. Trafalis8Laboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, GreeceDepartment of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, GreeceDepartment of Electron Microscopy & Molecular Pathology, The Cyprus Institute of Neurology & Genetics, 2371 Nicosia, CyprusLaboratory of Pharmacology, Medical School, National & Kapodistrian University of Athens, 11527 Athens, Greece(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.https://www.mdpi.com/2072-6694/12/5/1263lactam steroidal alkylating estersaniline-mustard alkylatorsmelphalanovarian carcinomaxenograftsERK |
| spellingShingle | Panagiotis Dalezis Eleni Geromichalou Aikaterini Polonifi Sofia Sagredou Nikolaos Nikoleousakos Michael Nikolaou Vasiliki Sarli Mihalis I. Panayiotidis Dimitrios T. Trafalis Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma Cancers lactam steroidal alkylating esters aniline-mustard alkylators melphalan ovarian carcinoma xenografts ERK |
| title | Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma |
| title_full | Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma |
| title_fullStr | Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma |
| title_full_unstemmed | Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma |
| title_short | Azasteroid Alkylators as Dual Inhibitors of AKT and ERK Signaling for the Treatment of Ovarian Carcinoma |
| title_sort | azasteroid alkylators as dual inhibitors of akt and erk signaling for the treatment of ovarian carcinoma |
| topic | lactam steroidal alkylating esters aniline-mustard alkylators melphalan ovarian carcinoma xenografts ERK |
| url | https://www.mdpi.com/2072-6694/12/5/1263 |
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