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Synergistic anticancer effects of the 9.2.27PE immunotoxin and ABT-737 in melanoma

Karianne Risberg1, Øystein Fodstad, Yvonne Andersson

  • 1Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Montebello, Oslo, Norway. Karianne.Risberg@rr-research.no

Plos One
|September 15, 2011
PubMed

Insights

Combining Pseudomonas exotoxin A (PE)-based immunotoxin 9.2.27PE with ABT-737 shows synergistic effects against melanoma cells, inducing apoptosis and delaying tumor growth in mice.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Combination therapy is a validated strategy to enhance anti-cancer efficacy.
  • Melanoma treatment requires novel therapeutic approaches targeting distinct cellular pathways.

Purpose of the Study:

  • To investigate the synergistic effects of 9.2.27PE and ABT-737 in melanoma.
  • To elucidate the mechanisms underlying the combination's cytotoxicity and in vivo efficacy.

Main Methods:

  • Melanoma cell lines were treated with 9.2.27PE and ABT-737 individually and in combination.
  • Apoptosis was assessed via caspase-3 activation, PARP inactivation, and DNA fragmentation.
  • Endoplasmic reticulum (ER) stress markers (GRP78, p-eIF2α) and intracellular calcium levels were measured.
  • Mcl-1 was silenced using short hairpin RNA (shRNA).
  • In vivo efficacy was evaluated in a human melanoma xenograft mouse model.

Main Results:

  • The combination of 9.2.27PE and ABT-737 exhibited synergistic cytotoxicity against melanoma cells.
  • Cell death was mediated by apoptosis, confirmed by inhibitor studies.
  • ABT-737 induced ER stress and increased intracellular calcium, effects amplified by 9.2.27PE.
  • Mcl-1 silencing potentiated ABT-737-induced calcium release and cytotoxicity.
  • The drug combination significantly delayed tumor growth in a xenograft mouse model.

Conclusions:

  • The combination of 9.2.27PE and ABT-737 demonstrates potent synergistic anti-melanoma activity.
  • The mechanism involves apoptosis induction, ER stress, and modulation of intracellular calcium.
  • This combination warrants further clinical investigation for melanoma treatment.

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