Investigational New Drugs

, Volume 30, Issue 4, pp 1471–1483

Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine (‘ecstasy’) through iterative chemical redesign: mechanisms and pathways to cell death

  • Agata M. Wasik
  • Michael N. Gandy
  • Matthew McIldowie
  • Michelle J. Holder
  • Anita Chamba
  • Anita Challa
  • Katie D. Lewis
  • Stephen P. Young
  • Dagmar Scheel-Toellner
  • Martin J. Dyer
  • Nicholas M. Barnes
  • Matthew J. Piggott
  • John Gordon
PRECLINICAL STUDIES

DOI: 10.1007/s10637-011-9730-5

Cite this article as:
Wasik, A.M., Gandy, M.N., McIldowie, M. et al. Invest New Drugs (2012) 30: 1471. doi:10.1007/s10637-011-9730-5

Summary

While 3,4-methylenedioxymethamphetamine (MDMA/‘ecstasy’) is cytostatic towards lymphoma cells in vitro, the concentrations required militate against its translation directly to a therapeutic in vivo. The possibility of ‘redesigning the designer drug’, separating desired anti-lymphoma activity from unwanted psychoactivity and neurotoxicity, was therefore mooted. From an initial analysis of MDMA analogues synthesized with a modified α-substituent, it was found that incorporating a phenyl group increased potency against sensitive, Bcl-2-deplete, Burkitt’s lymphoma (BL) cells 10-fold relative to MDMA. From this lead, related analogs were synthesized with the ‘best’ compounds (containing 1- and 2-naphthyl and para-biphenyl substituents) some 100-fold more potent than MDMA versus the BL target. When assessed against derived lines from a diversity of B-cell tumors MDMA analogues were seen to impact the broad spectrum of malignancy. Expressing a BCL2 transgene in BL cells afforded only scant protection against the analogues and across the malignancies no significant correlation between constitutive Bcl-2 levels and sensitivity to compounds was observed. Bcl-2-deplete cells displayed hallmarks of apoptotic death in response to the analogues while BCL2 overexpressing equivalents died in a caspase-3-independent manner. Despite lymphoma cells expressing monoamine transporters, their pharmacological blockade failed to reverse the anti-lymphoma actions of the analogues studied. Neither did reactive oxygen species account for ensuing cell death. Enhanced cytotoxic performance did however track with predicted lipophilicity amongst the designed compounds. In conclusion, MDMA analogues have been discovered with enhanced cytotoxic efficacy against lymphoma subtypes amongst which high-level Bcl-2—often a barrier to drug performance for this indication—fails to protect.

Keywords

ApoptosisBcl-2CytotoxicityLymphomaMDMA

Abbreviations

ABC

Activated B-Cell-like

BL

Burkitt’s lymphoma

DAT

Dopamine transporter

DLBCL

Diffuse large B-cell lymphoma

EBV

Epstein-Barr virus

FL

Follicular lymphoma

GCB

Germinal B-Cell-like

MDMA

3,4-methylenedioxymethamphetamine

NHL

Non-Hodgkin lymphomas

PARP

Poly (ADP-ribose) polymerase

PI

Propidium iodide

PTLD

Post-transplant lymphoproliferative disease

SERT

Serotonin transporter

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Agata M. Wasik
    • 1
  • Michael N. Gandy
    • 2
  • Matthew McIldowie
    • 2
  • Michelle J. Holder
    • 1
  • Anita Chamba
    • 1
  • Anita Challa
    • 1
  • Katie D. Lewis
    • 2
  • Stephen P. Young
    • 1
  • Dagmar Scheel-Toellner
    • 1
  • Martin J. Dyer
    • 3
  • Nicholas M. Barnes
    • 4
  • Matthew J. Piggott
    • 2
  • John Gordon
    • 1
  1. 1.School of Immunity & Infection, The Medical School, BirminghamUniversity of BirminghamBirminghamUK
  2. 2.School of Biomedical, Biomolecular and Chemical SciencesThe University of Western AustraliaCrawleyAustralia
  3. 3.Medical Research Council Toxicology UnitLeicesterUK
  4. 4.Cellular and Molecular Neuropharmacology Research Group, Clinical and Experimental MedicineThe Medical SchoolBirminghamUK