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Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1

Rico K H Lo1, Yok-Lam Kwong

  • 1Department of Medicine, Queen Mary Hospital, University of Hong Kong, Professorial Block, Pokfulam Road, Hong Kong, China.

Annals of Hematology
|August 17, 2013
PubMed

Insights

Arsenic trioxide (As2O3) effectively triggers apoptosis in mantle cell lymphoma (MCL) by suppressing cyclin D1. This targeted approach offers a potential new treatment for this aggressive cancer.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with a poor prognosis.
  • Overexpression of cyclin D1, driven by the t(11;14) translocation, is a hallmark of MCL.

Purpose of the Study:

  • To investigate the in vitro anti-cancer activities of arsenic trioxide (As2O3) in mantle cell lymphoma.
  • To elucidate the molecular mechanisms underlying As2O3's effects on MCL cells.

Main Methods:

  • Treatment of MCL cell lines (Jeko-1, Granta-519) with varying doses and durations of As2O3.
  • Analysis of apoptosis, cyclin D1 levels, cell cycle progression, and protein phosphorylation.
  • Investigation of signaling pathways involving glycogen synthase kinase-3beta (GSK-3β) and IκB kinase (IKK).
  • Validation in primary MCL patient samples.

Main Results:

  • As2O3 induced dose- and time-dependent apoptosis in MCL cell lines.
  • As2O3 suppressed cyclin D1 levels, leading to decreased retinoblastoma protein phosphorylation and G1 cell cycle arrest.
  • As2O3 did not affect cyclin D1 gene transcription but promoted its degradation via GSK-3β and IKK activation, resulting in cyclin D1 poly-ubiquitination and proteasomal breakdown.
  • These effects were partially replicated in refractory primary MCL samples.

Conclusions:

  • Arsenic trioxide demonstrates significant anti-proliferative and pro-apoptotic effects in mantle cell lymphoma models.
  • The mechanism involves the degradation of cyclin D1 through the activation of GSK-3β and IKK signaling pathways.
  • As2O3 shows potential as a therapeutic agent for mantle cell lymphoma, particularly in treatment-refractory cases.

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