Protective and anticancer effects of orange peel extract and naringin in doxorubicin treated esophageal cancer stem cell xenograft tumor mouse model

Background: chemotherapy drugs are the common therapy for cancer cells with side effects. Recent studies reported that natural products may contribute to decreasing the side effects of chemotherapy drugs. Here, we aimed to investigate the effects of orange peel extract (OPE) and its main compound; naringin (NR) to protect the side effects of doxorubicin (Dox) in esophageal cancer stem cells (CSCs) derived tumors in vivo. Methods: for this purpose, Esophageal cancer cell (YM1) derived spheres were treated in vitro with OPE, NR, Dox, Dox in combination with OPE or NR. The cell viability was assessed by XTT and the apoptosis was measured using Annexin/7-AAD and the cell cycle was also quantified by using PI staining method. The pluripotency related genes expression was carried out using qRT-PCR The protective effects of OPE and NR were evaluated by body weight evaluation and oxidative stress factors: malondialdehyde (MDA), total antioxidant capacity (TAC) and superoxide dismutase (SOD) measurement in xenograft mice tumor model injected with Dox. Results: ESCC CSCs overexpress SOX2 and OCT4 pluripotency genes. OPE or NR can protect the cellular toxicity of Dox in vitro mainly by decreasing cellular apoptosis of ESCC CSCs however S-phase cell cycle arrest has not been affected significantly. In vivo experiments revealed that the use of Dox simultaneously with OPE or NR not only can reduce the tumor size but also the body weight of the treated nude mice were maintained in comparison to Dox alone. In contrast to Dox alone, Dox in combination with OPE or NR showed less systemic toxicity and decreased oxidative stress fraction circulation, however, OPE seemed as more protective. Conclusion: The results suggest that these natural compounds can be used as adjuvant therapy to lower systemic toxicity of chemotherapeutic agents like DOX in ESCC cancer stem cells treatment.