Molecular Modeling-(B)ased Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells


Maki M. A. A. , Kumar P. V. , Cheah S., Wei Y. S. , Al-Nema M., Bayazeid O., ...Daha Fazla

ACS OMEGA, cilt.4, sa.5, ss.8767-8777, 2019 (SCI İndekslerine Giren Dergi) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 4 Konu: 5
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1021/acsomega.9b00109
  • Dergi Adı: ACS OMEGA
  • Sayfa Sayıları: ss.8767-8777

Özet

Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the beta-cyclodextrin (beta-CD): FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, beta-CD, and FGF7. Molecular docking insights revealed that beta-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 +/- 0.23 mu M) when compared to the aqueous solubility of pure EV (1.7 +/- 0.16 mu M). In addition, the in vitro cytotoxic activity of a FGF7: beta-CD: EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7: beta-CD: EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of beta-CD: FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 +/- 1.42 to 1.87 +/- 0.33 mu M when compared to FGF7: beta-CD: EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the beta-CD: FGF7 complex and EV as an effective treatment to combat CRC.