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Pyrimethamine sensitizes pituitary adenomas cells to temozolomide through cathepsin B-dependent and caspase-dependent

Congxin Dai1, Bo Zhang, Xiaohai Liu

  • 1Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

International Journal of Cancer
|April 9, 2013
PubMed

Insights

Pyrimethamine (PYR) combined with temozolomide (TMZ) shows synergistic antitumor effects against invasive pituitary adenomas (PAs). This novel combination therapy enhances efficacy and survival rates in preclinical models, offering hope for refractory PA cases.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Invasive pituitary adenomas (PAs) are challenging to treat and often resistant to standard therapies like temozolomide (TMZ).
  • Pyrimethamine (PYR), known for antiprotozoan effects, exhibits potent antitumor activity, particularly in combination with TMZ in other cancers.

Purpose of the Study:

  • To evaluate the efficacy of pyrimethamine (PYR) and temozolomide (TMZ) alone and in combination against invasive pituitary adenoma (PA) cell lines and a xenograft model.
  • To elucidate the underlying mechanisms of synergistic antitumor activity induced by the TMZ/PYR combination.

Main Methods:

  • In vitro studies using rat/mouse PA cell lines (αT3-1, GH3, MMQ, ATt-20) treated with TMZ, PYR, or their combination.
  • In vivo evaluation in a GH3 xenograft tumor model to assess antitumor activity, survival rates, and systemic side effects.
  • Analysis of cell cycle, DNA damage, apoptosis-related protein expression (e.g., BAX, Bcl-2, PARP, histone H2AX), caspase activities, and cathepsin B levels.

Main Results:

  • The TMZ/PYR combination synergistically inhibited PA cell proliferation and invasion, and induced apoptosis in vitro.
  • In vivo, the combination demonstrated significant antitumor activity and improved survival in the GH3 xenograft model without increased systemic toxicity.
  • Mechanistically, the combination induced cell cycle arrest, DNA damage, and apoptosis through both cathepsin B-dependent and caspase-dependent pathways, evidenced by altered protein expression and enzyme activities.

Conclusions:

  • Pyrimethamine (PYR) potentiates the efficacy of temozolomide (TMZ) in treating invasive pituitary adenomas (PAs).
  • The synergistic effect involves the induction of apoptosis via cathepsin B and caspase-dependent pathways.
  • The combination of PYR and TMZ represents a promising novel therapeutic strategy for invasive PAs resistant to conventional treatments.
Keywords:
folate metabolisminvasive pituitary adenomaspyrimethaminerefractorytemozolomide

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