OncoTargets and Therapy (Dec 2020)

Novel Small Molecular Compound AE-848 Potently Induces Human Multiple Myeloma Cell Apoptosis by Modulating the NF-κB and PI3K/Akt/mTOR Signaling Pathways

  • Xu Y,
  • Feng X,
  • Zhou Q,
  • Jiang W,
  • Dai Y,
  • Jiang Y,
  • Liu X,
  • Li S,
  • Wang Y,
  • Wang F,
  • Li A,
  • Zheng C

Journal volume & issue
Vol. Volume 13
pp. 13063 – 13075

Abstract

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Yaqi Xu,1– 3 Xiaoli Feng,4 Qian Zhou,1,2,5 Wen Jiang,1,2,6 Yibo Dai,1– 3 Yang Jiang,1– 3 Xiaoli Liu,1– 3 Shuo Li,1,2,7 Yongjing Wang,1– 3 Fang Wang,6 Ai Li,1– 3 Chengyun Zheng1– 3 1Department of Hematology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Institute of Biotherapy for Hematological Malignancies, Shandong University, Jinan, Shandong, People’s Republic of China; 3Shandong University-Karolinska Institute Collaboration Laboratory for Stem Cell Research, Jinan, Shandong, People’s Republic of China; 4Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 5Department of Hematology, Linyi Central Hospital, Linyi, Shandong, People’s Republic of China; 6Institute of Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 7Binzhou Medical University Hospital, Binzhou, Shandong, People’s Republic of ChinaCorrespondence: Chengyun Zheng; Ai LiHematology Department of the Second Hospital of Shandong University, 247th of Beiyuan Road, Jinan, Shandong, People’s Republic of ChinaTel +86 13675319282; +86 176 6008 0688Email [email protected]; [email protected]: We aimed to investigate the anti-multiple myeloma (MM) activity of the new small molecular compound AE-848 (5-bromo-2-hydroxyisophthalaldehyde bis[(1-methyl-1H-benzimidazol-2-yl)hydrazone]) and its underlying anti-MM mechanism.Methods: Cell viability and apoptosis were detected and quantified by using MTT and flow cytometry, respectively. JC-1 dye-related techniques were used to assess mitochondrial membrane potential (MMP). Western blotting was applied to detect the expression of NF-κB and PI3K/Akt/mTOR pathway-associated proteins. The in vivo activity of AE-848 against MM was evaluated in a MM mouse model.Results: Application of AE-848 into the in vitro cell culture system significantly reduced the viability and induced apoptosis of the MM cell lines, RPMI-8226 and U266, in a dose- and time-dependent manner, respectively. JC-1 dye and Western blotting analysis revealed that AE-848 induced the cleavage of caspase-8, caspase-3, and poly ADP-ribose polymerase (PARP), resulting in loss of mitochondrial membrane potential (MMP). Both the NF-κB and PI3K/AKT/mTOR signaling pathways were involved in AE-848-induced apoptosis of U266 and RPMI8226 cells. Moreover, AE-848 leads to cell cycle arrest of MM cells. Its anti-MM efficacy was further confirmed in a xenograft model of MM. AE-848 administration significantly inhibited MM tumor progression and prolonged the survival of MM-bearing mice. More importantly, our results demonstrated that AE-848 markedly induced primary MM cell apoptosis.Conclusion: Our results for the first time showed that the small compound AE-848 had potent in vitro and in vivo anti-myeloma activity, indicating that AE-848 may have great potential to be developed as a drug for MM treatment.Keywords: small molecular compound, AE-848, multiple myeloma, apoptosis, NF-κB and PI3K/Akt/mTOR pathway

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