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Open AccessArticle

Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer

1
Department of Life Science and Institute of Biotechnology, National Dong Hwa University, Hualien 97401, Taiwan
2
Neural Regeneration Laboratory, Neurological Institute, Taipei Veterans General Hospital, Taipei 11217, Taiwan
3
Department of Chemistry, National Dong Hwa University, Hualien 97401, Taiwan
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2018, 7(10), 321; https://doi.org/10.3390/jcm7100321
Received: 5 September 2018 / Revised: 21 September 2018 / Accepted: 30 September 2018 / Published: 3 October 2018
(This article belongs to the Section Molecular Diagnostics)
Prodigiosin (PG) belongs to a family of prodiginines isolated from gram-negative bacteria. It is a water insoluble red pigment and a potent proapoptotic compound. This study elucidates the anti-tumor activity and underlying mechanism of PG in doxorubicin-sensitive (Dox-S) and doxorubicin-resistant (Dox-R) lung cancer cells. The cytotoxicity and cell death characteristics of PG in two cells were measured by MTT assay, cell cycle analysis, and apoptosis/autophagic marker analysis. Then, the potential mechanism of PG-induced cell death was evaluated through the phosphatidylinositol-4,5-bisphosphate 3-kinase-p85/Protein kinase B /mammalian target of rapamycin (PI3K-p85/Akt/mTOR) and Beclin-1/phosphatidylinositol-4,5-bisphosphate 3-kinase-Class III (Beclin-1/PI3K-Class III) signaling. Finally, in vivo efficacy was examined by intratracheal inoculation and treatment. There was similar cytotoxicity with PG in both Dox-S and Dox-R cells, where the half maximal inhibitory concentrations (IC50) were all in 10 μM. Based on a non-significant increase in the sub-G1 phase with an increase of microtubule-associated proteins 1A/1B light chain 3B-phosphatidylethanolamine conjugate (LC3-II), the cell death of both cells was categorized to achieve autophagy. Interestingly, an increase in cleaved-poly ADP ribose polymerase (cleaved-PARP) also showed the existence of an apoptosis-sensitive subpopulation. In both Dox-S and Dox-R cells, PI3K-p85/Akt/mTOR signaling pathways were reduced, which inhibited autophagy initiation. However, Beclin-1/PI3K-Class III downregulation implicated non-canonical autophagy pathways were involved in PG-induced autophagy. At completion of the PG regimen, tumors accumulated in the mice trachea and were attenuated by PG treatment, which indicated the efficacy of PG for both Dox-S and Dox-R lung cancer. All the above results concluded that PG is a potential chemotherapeutic agent for lung cancer regimens regardless of doxorubicin resistance. View Full-Text
Keywords: prodigiosin; doxorubicin resistant; lung cancer; intratracheal inoculation prodigiosin; doxorubicin resistant; lung cancer; intratracheal inoculation
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MDPI and ACS Style

Chiu, W.-J.; Lin, S.-R.; Chen, Y.-H.; Tsai, M.-J.; Leong, M.K.; Weng, C.-F. Prodigiosin-Emerged PI3K/Beclin-1-Independent Pathway Elicits Autophagic Cell Death in Doxorubicin-Sensitive and -Resistant Lung Cancer. J. Clin. Med. 2018, 7, 321.

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