Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin

• Published in: Molecules (Basel, Switzerland) Switzerland), 2021-12, Vol.27 (1), p.90
• Main Authors: Abdalla, Ashraf N, Di Stefano, Miriana, Poli, Giulio, Tuccinardi, Tiziano, Bader, Ammar, Vassallo, Antonio, Abdallah, Mohamed E, El-Readi, Mahmoud Zaki, Refaat, Bassem, Algarni, Alanood S, Ahmad, Rizwan, Alkahtani, Hamad M, Abdel-Aziz, Alaa A-M, El-Azab, Adel S, Alqathama, Aljawharah
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Binding Sites; Biocompatibility; Breast cancer; Cancer therapies; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Chemosensitization; Chemotherapy; Combinatorial analysis; Cytotoxicity; Diketones; Dose-Response Relationship, Drug; Doxorubicin; Doxorubicin - pharmacology; Drug dosages; Drug resistance; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Efflux; Glycoproteins; Heat shock proteins; Hsp90; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Hsp90 protein; Humans; In vivo methods and tests; Inhibitory Concentration 50; Investigations; isatin; Isatin - analogs & derivatives; Isatin - chemistry; Isatin - pharmacology; Kinases; MCF-7 Cells; MDR; Modelling; Models, Molecular; Molecular Conformation; Molecular modelling; Molecular Structure; Multidrug resistance; Natural products; P-gp; Pharmaceutical industry; Pharmacokinetics; Protein Binding; Proteins; Rhodamine; Selectivity; Structure-Activity Relationship; Surface plasmon resonance; synergism with doxorubicin
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27010090

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA , at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA stably interacted with Hsp90α more efficiently compared with 17- -allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-κB) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA to confirm its anticancer capabilities.