Some 2-[4-(<i>1H</i>-benzimidazol-1-yl) phenyl]-<i>1H</i>-benzimidazole derivatives overcome imatinib resistance by induction of apoptosis and reduction of P-glycoprotein activity

Hekmatshoar Y., Ozkan T., Alp M., Gurkan-Alp A. S., Sunguroglu A.

CHEMICAL BIOLOGY & DRUG DESIGN, cilt.102, sa.6, ss.1521-1533, 2023 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 102 Sayı: 6
  • Basım Tarihi: 2023
  • Doi Numarası: 10.1111/cbdd.14343
  • Dergi Adı: CHEMICAL BIOLOGY & DRUG DESIGN
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE, Veterinary Science Database
  • Sayfa Sayıları: ss.1521-1533
  • Anahtar Kelimeler: benzimidazole, chronic myeloid leukemia, drug resistance, imatinib, BENZIMIDAZOLE DERIVATIVES, ANTICANCER, MECHANISMS, LEUKEMIA, DNA, INHIBITORS, BIOLOGY, SYSTEM, DRUGS
  • Ankara Üniversitesi Adresli: Evet

Özet

Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) introduced for the chronic myeloid leukemia (CML) therapy. Emergence of IMA resistance leads to the relapse and failure in CML therapy. Benzimidazole is a heterocyclic organic compound which is widely investigated for the development of anticancer drugs. In this study, we aimed to explore the anticancer effects of some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives on K562S (IMA-sensitive) and K562R (IMA-resistant) cells. To analyze the cytotoxic and apoptotic effects of the compounds, K562S, K562R, and L929 cells were exposed to increasing concentrations of the derivatives. Cytotoxic effects of compounds on cell viability were analyzed with MTT assay. Apoptosis induction, caspase3/7 activity were investigated with flow cytometry and BAX, BIM, and BAD genes expression levels were analyzed with qRT-PCR. Rhodamine123 (Rho-123) staining assays were carried out to evaluate the effect of compounds on P-glycoprotein (P-gp) activity. The hit compounds were screened using molecular docking, and the binding preference of each compounds to BCR-ABL protein was evaluated. Our results indicated that compounds triggered cytotoxicity, caspase3/7 activation in K562S and K562R cells. Rho-123 staining showed that compounds inhibited P-gp activity in K562R cells. Overall, our results reveal some benzimidazole derivatives as potential anticancer agents to overcome IMA resistance in CML.