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Endocrine Abstracts (2019) 63 P12 | DOI: 10.1530/endoabs.63.P12

ECE2019 Poster Presentations Adrenal and Neuroendocrine Tumours 1 (60 abstracts)

Combined autophagy and mTOR inhibition reduces cells proliferation and induces apoptosis in a lung carcinoid in-vitro model

Adi Knigin , Shani Avniel-Polak , David J Gross & Simona Grozinsky-Glasberg

Hadassah-Hebrew University Medical Center, Neuroendocrine Tumor Unit, Jerusalem, Israel.

Introduction: Treatment options for patients with metastatic lung carcinoids (LC) are limited. Everolimus (RAD001), an mTOR inhibitor (mTORi) which suppresses tumor cells growth & proliferation, appears to be efficient in these patients; however, it promotes autophagy, thereby paradoxically supporting tumor cell survival and development of drug-resistance. We have previously demonstrated in a BON1 pancreatic NEN model that adding chloroquine (CQ, an autophagy inhibitor) to mTORi inhibited cell proliferation and induced apoptosis compared to mTORi alone.

Aim(s): To investigate the effect of CQ ± mTORi on LC cell viability, proliferation and apoptosis.

Materials and methods: The LC cell line NCI-H727 was treated with CQ, RAD001 and Torin1, alone or in combination. Cell viability and proliferation were examined by XTT and Ki67 staining. Flow cytometry and Western blot were used to assess drug effects on cell cycle, apoptosis, PI3K/Akt/mTOR and autophagy pathways. The effect of differential timing of drug administration was examined by using a cytotoxicity kit.

Results: CQ alone reduced LC cell viability by ~ 30%; the addition of CQ to RAD001 or Torin1 significantly reduced cell viability by 60% and 98%, respectively. Torin1 or RAD001 combined with CQ induced a higher degree of apoptosis and accumulation of LC3-II (a marker of autophagy). Our results imply that the inhibition of cell proliferation may result from CQ effects on cytosol and lysosomes nutrient content causing an indirect inhibition of mTOR.

Conclusion: In the present LC model, CQ alone and mainly in addition to a mTORi, promotes apoptosis and suppresses cell proliferation, potentiating the effect of mTORi. Further experiments are needed to understand the role of CQ in the treatment arsenal of patients with metastatic LC.

Volume 63

21st European Congress of Endocrinology

Lyon, France
18 May 2019 - 21 May 2019

European Society of Endocrinology 

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