Effective Targeting of Glutamine Synthetase with Amino Acid Analogs as a Novel Therapeutic Approach in Breast Cancer

被引：1

作者：

Abdelsattar, Shimaa ^{[1
]}

Al-Amodi, Hiba S. ^{[2
]}

Kamel, Hala F. ^{[2
,3
]}

Al-Eidan, Ahood A. ^{[4
]}

Mahfouz, Marwa M. ^{[5
]}

El Khashab, Kareem ^{[6
]}

Elshamy, Amany M. ^{[7
]}

Basiouny, Mohamed S. ^{[8
]}

Khalil, Mohamed A. ^{[9
]}

Elawdan, Khaled A. ^{[10
]}

Elsaka, Shorouk ^{[10
]}

Mohamed, Salwa E. ^{[10
]}

Khalil, Hany ^{[10
]}

机构：

[1] Menoufia Univ, Natl Liver Inst, Clin Biochem & Mol Diagnost Dept, Shibin Al Kawm 32511, Egypt

[2] Umm Al Qura Univ, Fac Med, Biochem Dept, Mecca 21955, Saudi Arabia

[3] Ain Shams Univ, Fac Med, Med Biochem & Mol Biol Dept, Cairo 11591, Egypt

[4] Imam Abdulrahman Bin Faisal Univ, Dept Biol, Coll Sci, Dammam 34212, Saudi Arabia

[5] Menoufia Univ, Fac Pharm, Dept Pharmacol & Toxicol, Shibin Al Kawm 32511, Egypt

[6] Badr Acad Sci & Technol, High Technol Inst Appl Hlth Sci, Med Lab Dept, Badr 11829, Egypt

[7] Badr Univ Cairo, Sch Allied Hlth Sci, Med Lab Sci Dept, Badr 11829, Egypt

[8] Badr Univ Cairo, Sch Biotechnol, Badr 11829, Egypt

[9] Cairo Univ, NCI, Clin Pathol Dept, Giza 12613, Egypt

[10] Univ Sadat City, Genet Engn & Biotechnol Res Inst, Dept Mol Biol, Sadat 32897, Egypt

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2025年 / 26卷 / 01期

关键词：

breast cancer; amino acid analogs; acivicin; azaserine; glutamine synthetase; METABOLISM; BRCA1;

D O I：

10.3390/ijms26010078

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Cancer cells undergo metabolic rewiring to support rapid proliferation and survival in challenging environments. Glutamine is a preferred resource for cancer metabolism, as it provides both carbon and nitrogen for cellular biogenesis. Recent studies suggest the potential anticancer activity of amino acid analogs. Some of these analogs disrupt cellular nucleotide synthesis, thereby inhibiting the formation of DNA and RNA in cancer cells. In the present study, we investigated the anticancer properties of Acivicin and Azaserine in the breast cancer MCF-7 cell line, comparing their effects to those on the non-tumorigenic MCF-10 epithelial cell line in vitro. Interestingly, at lower concentrations, both Acivicin and Azaserine showed potent inhibition of MCF-7 cell proliferation, as assessed by the MTT assay, without detectable toxicity to normal cells. In contrast, Sorafenib (Nexavar), a commonly used drug for solid tumors, showed harmful effects on normal cells, as indicated by increased lactate dehydrogenase (LDH) production in treated cells. Furthermore, unlike Sorafenib, treatment with Acivicin and Azaserine significantly affected apoptotic signaling in treated cells, indicating the role of both amino acid analogs in activating programmed cell death (PCD), as assessed by the Annexin-V assay, DAPI staining, and the relative expression of tumor suppressor genes PTEN and P53. ELISA analysis of MCF-7 cells revealed that both Acivicin and Azaserine treatments promoted the production of anti-inflammatory cytokines, including IL-4 and IL-10, while significantly reducing the production of tumor necrosis factor alpha (TNF-alpha). Mechanistically, both Acivicin and Azaserine treatment led to a significant reduction in the expression of glutamine synthetase (GS) at both the RNA and protein levels, resulting in a decrease in intracellular glutamine concentrations over time. Additionally, both treatments showed comparable effects on Raf-1 gene expression and protein phosphorylation when compared with Sorafenib, a Raf-1 inhibitor. Moreover, docking studies confirmed the strong binding affinity between Acivicin, Azaserine, and glutamine synthetase, as evidenced by their docking scores and binding interactions with the enzyme crystal. Collectively, these findings provide evidence for the anticancer activity of the two amino acid analogs Acivicin and Azaserine as antagonists of glutamine synthetase, offering novel insights into potential therapeutic strategies for breast cancer.

引用

页数：17