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Combining chloroquine with RAD001 inhibits tumor growth in a NEN mouse model

Shani Avniel-Polak1, Gil Leibowitz1, Victoria Doviner2

  • 1Neuroendocrine Tumor LaboratoryEndocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Endocrine-Related Cancer
|April 12, 2018
PubMed

Insights

Chloroquine enhances RAD001 (everolimus) efficacy in neuroendocrine neoplasms (NENs) by inhibiting autophagy. This combination therapy reduced tumor growth and increased cancer cell death, suggesting potential for clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Neuroendocrine neoplasms (NENs) treatment is often hindered by drug resistance.
  • mTOR inhibitors (mTORi) like RAD001 show anti-neoplasm effects but can stimulate autophagy, a survival mechanism for cancer cells.
  • Chloroquine (CQ) inhibits autophagy, offering a potential strategy to overcome resistance.

Purpose of the Study:

  • To investigate the anti-tumorigenic effects of chloroquine (CQ), alone and in combination with RAD001 (everolimus).
  • To determine if CQ enhances RAD001 efficacy by inhibiting autophagy in a neuroendocrine neoplasm (NEN) model.

Main Methods:

  • A subcutaneous xenograft mouse model of NEN was established.
  • Tumor growth, mTOR pathway activity, autophagy markers, and apoptosis were evaluated after treatment with CQ, RAD001, or combination therapy.
  • Histopathological analysis was performed.

Main Results:

  • Both CQ and RAD001 significantly reduced NEN tumor volume.
  • The combination of CQ and RAD001 demonstrated enhanced anti-tumorigenic effects.
  • Combined treatment markedly inhibited mTOR activity, suppressed neoplasm cell growth, increased autophagosome accumulation, and promoted apoptosis.

Conclusions:

  • Chloroquine (CQ) potentiates the anti-tumorigenic effects of RAD001 (everolimus) in neuroendocrine neoplasms (NENs) by inhibiting autophagy.
  • The combination therapy warrants further investigation in clinical trials for NEN patients, particularly those treated with mTOR inhibitors.
Keywords:
RAD001autophagychloroquinemTOR inhibitorsneuroendocrine neoplasms

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