Abstract
Synergistic effects between natural compounds and chemotherapy drugs are believed to have fewer side effects with equivalent efficacy. However, the synergistic potential of prodigiosin (PG) with doxorubicin (Dox) chemotherapy is still unknown. This study explores the synergistic mechanism of PG and Dox against oral squamous cell carcinoma (OSCC) cells. Three OSCC cell lines were treated with different PG/Dox combinatory schemes for cytotoxicity tests and were further investigated for cell death characteristics by cell cycle flow cytometry and autophagy/apoptosis marker labelling. When OSCC cells were pretreated with PG, the cytotoxicity of the subsequent Dox-treatment was 30% higher than Dox alone. The cytotoxic efficacy of PG-pretreated was found better than those of PG plus Dox co-treatment and Dox-pretreatment. Increase of Sub-G1 phase and caspase-3/LC-3 levels without poly (ADP-ribose) polymeras (PARP) elevation indicated both autophagy and necrosis occurred in OSCC cells. Dox flux after PG-priming was further evaluated by rhodamine-123 accumulation and Dox transporters analysis to elucidate the PG-priming effect. PG-priming autophagy enhanced Dox accumulation according to the increase of rhodamine-123 accumulation without the alterations of Dox transporters. Additionally, the cause of PG-triggered autophagy was determined by co-treatment with endoplasmic reticulum (ER) stress or AMP-activated protein kinase (AMPK) inhibitor. PG-induced autophagy was not related to nutrient deprivation and ER stress was proved by co-treatment with specific inhibitor. Taken together, PG-priming autophagy could sensitize OSCC cells by promoting Dox influx without regulation of Dox transporter. The PG-priming might be a promising adjuvant approach for the chemotherapy of OSCC.
Highlights
Doxorubicin (Adriamycin, Dox), isolated from soil bacteria Streptomyces peucetius, is the first member of anthracyclines [1,2]
Cell lines used in this study were obtained from different sources: Human pharynx squamous carcinoma FaDu from Dr Chun-Shu Lin (Radiation Oncology Department, Tri-Service General Hospital, Taipei, Taiwan), human oral squamous cell carcinoma cell line OECM1 and tongue carcinoma cell line SAS from Professor Ta-Chun Yuan (Department of Life Science, National Dong Hwa University, Hualien, Taiwan), and human bronchus epithelial cell BEAS-2b from American Type Culture Collection (ATCC)
Three combined manners of PG/Dox were tested in oral squamous cell carcinoma (OSCC)
Summary
Doxorubicin (Adriamycin, Dox), isolated from soil bacteria Streptomyces peucetius, is the first member of anthracyclines (including daunorubicin, epirubicin, and idarubicin) [1,2]. Dox can import into cells through solute carrier family 22 member 16 (SLC22A16, known organic cation transporter 6, oct-6) and export by ATP-binding cassette transporter family members, in which multidrug-related protein 1 (MDR-1 or p-glycoprotein) and breast cancer resistance protein (BCRP or ABCG2) are involved [3]. These proteins will be regulated (upregulation of exporter and downregulation of importer) during long-term exposure to a non-toxic dose of Dox [18]. The application of PG as an adjuvant in chemotherapy is still unknown
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