Rumex vesicarius L. boosts the effectiveness of sorafenib in triple-negative breast cancer by downregulating BCl2, mTOR, and JNK, and upregulating p21 expression

Aml Ghanem; Mohamed A Ali; Mohamed A Elkady; Sherif S Abdel Mageed; Mahmoud A El Hassab; Mohamed K El-Ashrey; Osama A Mohammed; Ahmed S Doghish

doi:10.1016/j.prp.2023.154807

Rumex vesicarius L. boosts the effectiveness of sorafenib in triple-negative breast cancer by downregulating BCl2, mTOR, and JNK, and upregulating p21 expression

Pathol Res Pract. 2023 Oct:250:154807. doi: 10.1016/j.prp.2023.154807. Epub 2023 Sep 9.

Authors

Aml Ghanem¹, Mohamed A Ali¹, Mohamed A Elkady², Sherif S Abdel Mageed³, Mahmoud A El Hassab⁴, Mohamed K El-Ashrey⁵, Osama A Mohammed⁶, Ahmed S Doghish⁷

Affiliations

¹ School of Biotechnology, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
² Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt. Electronic address: mohamedelkady1565.el@azhar.edu.eg.
³ Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), SouthSinai, Ras Sudr 46612, Egypt.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, King Salman International University (KSIU), SouthSinai, Ras Sudr 46612, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt.
⁶ Department of Clinical Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia.
⁷ Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11231, Egypt. Electronic address: ahmed_doghish@azhar.edu.eg.

PMID: 37696244
DOI: 10.1016/j.prp.2023.154807

Abstract

Background/aim: Triple-negative breast cancer (TNBC) is characterized by poor prognosis, rapid progression, serious clinical behavior, an elevated risk of metastasis, and resistance to standard treatments. Traditional medicine practitioners value Rumex vesicarius L. (RMV) for a variety of reasons, including the plant's antioxidant capabilities. Our study's goals were to ascertain the efficacy of RMV alone and in combination with sorafenib (SOR) against the aggressive TNBC cell line (MDA-MB-231) and use in vitro and in silico analysis to deduce the fundamental mechanism of action.

Methods: In the current study, molecular operating environment (MOE, 2019.0102) software was used for performing molecular docking. The MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to determine the cytotoxicity of RMV, SOR or RMV/SOR combination against the TNBC cell line MDA-MB-231 cells. The effects of RMV, SOR, and RMV and SOR combining on mRNAs expressions of the target genes including mTOR, p21, JNK, and BCl2 were evaluated. In TNBC cells, the relative expressions of mRNAs of the genes were examined by using real-time quantitative polymerase chain reaction (RT-qPCR).

Results: In our experiments, we discovered that both RMV extracts alone and in combination with SOR considerably reduced cancer cell proliferation (IC₅₀ = 0.83 and 0.19 μM, respectively). Additionally, the expression of the tumor suppressor gene p21 was elevated whereas the expression of the invasion and anti-apoptosis genes BCl2, mTOR, and JNK were significantly decreased after treatment with RMV and SOR. Based on in silico analysis, it was found that RMV extract contains bioactive chemicals with a high affinity for inhibiting JNK and VEGFR-2.

Conclusion: In conclusion, in vitro and in silico investigations show that the RMV extract improves the anticancer efficiency of SOR through molecular processes involving the downregulation of mTOR, BCl2, and JNK1 and overexpression of p21 tumor suppressor gene. Finally, we suggest conducting additional in vivo investigations on RMV and its bioactive components to verify their potential in cancer therapy.

Keywords: BCl2; JNK; Rumex vesicarius L.; Sorafenib; VEGFR-2; mTOR.