Abstract
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.
Highlights
For many years in the United States, lung cancer and breast cancer have ranked first and second, respectively, for new cancer cases and deaths
According to the origin and morphology of cancer cells, lung cancer can be classified as small cell lung carcinoma (SCLC) or non-small cell lung carcinoma (NSCLC), with 80–85%
Dox-R and Dox-S cells were exposed to various concentrations of PG and Dox for measuring the cell viability by MTT assay
Summary
For many years in the United States, lung cancer and breast cancer have ranked first and second, respectively, for new cancer cases and deaths. For lung cancer in particular, it is estimated that there are fewer new cases than breast cancer, but the estimated number of deaths is almost 4 times higher than breast cancer [1]. According to the origin and morphology of cancer cells, lung cancer can be classified as small cell lung carcinoma (SCLC) or non-small cell lung carcinoma (NSCLC), with 80–85%. Of lung cancer patients categorized as NSCLC [1,2,3]. Recent statistical results showed that 52% of lung cancer patients are non-smokers, especially in women [6]. Non-significant symptoms and alteration of lung cancer epidemiology increases the difficulty of lung cancer diagnosis [7] and influences the timing of treatment and survival rates
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