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Lung Cancer |

Inhibition of Autophagy Enhances Apoptotic Potential of Pemetrexed and Simvastatin in Malignant Mesothelioma and Lung Cancer Cells FREE TO VIEW

Ki Eun Hwang; Hak-Ryul Kim; Eun-Taik Jeong
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Wonkwang University Hospital, Iksan City, Republic of Korea


Chest. 2014;146(4_MeetingAbstracts):584A. doi:10.1378/chest.1992708
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Abstract

SESSION TITLE: Lung Cancer Posters I

SESSION TYPE: Original Investigation Poster

PRESENTED ON: Wednesday, October 29, 2014 at 01:30 PM - 02:30 PM

PURPOSE: Pemetrexed is a multitarget antifolate for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC) and has been shown to stimulate autophagy. In this study, we determined whether combination treatment with pemetrexed and simvastatin can induce autophagy in malignant mesothelioma and NSCLC cells. Furthermore, we determined whether inhibition of autophagy can drive malignant mesothelioma and NSCLC cells into apoptosis.

METHODS: Malignant mesothelioma cells MSTO-211 and NSCLC cells A549 were treated with pemetrexed and simvastatatin alone and in combination, and their effect on apoptosis was evaluated. Autophagy was assessed by transmission electron microscopy and confocal microscopy for GFP-LC3 and acridine orange. Autophagic induction by pemetrexed and simvastatatin was also investigated using autophagic inhibitors or inducers, the proportion of apoptotic cells was further determined by Annexin V assay.

RESULTS: Combination of pemetrexed and simvastatatin induced more caspase dependent apoptosis and autophagy than either drug in malignant mesothelioma and NSCLC cells. 3-methyladenine (3-MA), bafilomycin A, E64d/pepstatin A, and ATG5 siRNA increased apoptotic potential of pemetrexed and simvastatatin whereas rapamycin and LY294002 decreased caspase dependent apoptosis of pemetrexed and simvastatatin.

CONCLUSIONS: Combination of pemetrexed and simvastatatin augments their apoptosis and autophagy in malignant mesothelioma and NSCLC cells. Inhibition of autophagy was shown to enhance apoptosis, suggesting a novel therapeutic strategy against malignant mesothelioma and lung cancer.

CLINICAL IMPLICATIONS: Inhibition of autophagy was shown to enhance apoptosis, suggesting a novel therapeutic strategy against malignant mesothelioma and lung cancer.

DISCLOSURE: The following authors have nothing to disclose: Ki Eun Hwang, Hak-Ryul Kim, Eun-Taik Jeong

No Product/Research Disclosure Information


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