Ivermectin Enhance Susceptibility Of Oral Squamous Cell Carcinoma To Cytotoxic Drugs

Objectives:Head and neck squamous cell carcinoma(SCC),as one of the most common malignant tumors of stomatology,often brings physical and mental pain to the patients because of its influence on facial features and language,chewing or swallowing functions.For nearly three decades,concepts such as molecular biological therapy and precise treatment rapidly develop,thus newer and better treatments are available for many cancers.Ho’wever,the treatment of head and neck SCC still has not made great progress.Although there are new drugs such as PD-L1 inhibitors and cetuximab,they still have shortcomings,for instance,expensive and having few independent experiments.The treatment of head and neck squamous cell carcinoma is currently surgery.Ivermectin,a dihydrogen derivative of abamectin,belongs to macrolide antibiotics.It has been widely used all over the world since it was approved as a human-application drug for the treatment of filariasis in 1987.Its security is guaranteed,pharmacology and toxicology experiment are relatively full,and some recent studies have shown that Ivermectin has good therapeutic effect on glioblastoma,breast cancer,ovarian cancer,leukemia,etc.And ivermectin exerts anti-tumor effect by inhibiting kpnβ1 gene and promoting apoptosis or other kinds of ways.The current academic circles have a view that targeted drugs for a single pathway may be associated with early drug resistance of the tumor.Therefore,ivermectin,which has a variety of anti-tumor mechanism,may be an auxiliary drug with good anti-tumor effect.And it has been applied in human for a long time,so it is promising enter clinical trials stage in a short time to benefit the public if the experiment proves that ivermectin has the resistance effect of tongue squamous cell carcinoma.This experiment first confirmed that ivermectin has anti-tumor effects in vitro experiments,then further confirmed that the ivermectin has combined effects with cisplatin or paclitaxel in vitro experiments,finally verified synergy of ivermectin and paclitaxel in vitro experiment.Methods:1.We chose tongue squamous cell carcinoma SCC25 and CAL27 as the research objects.CCK8 and plate clone formation assay were used to confirm the ivermectin inhibits the proliferation of tongue squamous cell cancer.Wound experiment and Transwell migration experiment were used to further determine the ivermectin inhibits migration ability of tongue squamous cell cancer cells.2.To further explore the effect of combination of ivermectin with cisplatin/paclitaxel on tongue squamous cell carcinoma,CCK8 experiment designed by Talalay-Chou median effect theorem was applied and CI value was calculated to determine the effect of drug combination.3.We constructed a nude mice subcutaneous tumor model,and established four dosing regimens,including control group,ivermectin group,paclitaxel group and combination group.The effect of the above drugs on tumors were determine by measuring the changes in tumor size,and the drug safety was evaluated according to the changes of the nude mice weight and dissection of important organs of each nude mice,through visual observation and organ coefficients.4.Western blotting was used to assess the expression level of KPNB1,and flow cytometry was used to analyze effect of ivermectin on apoptosis,then we preliminary explored the anti-tumor mechanism of ivermectin.Results:1.Ivermectin exerted an inhibitory effect on the proliferation and migration of tongue squamous cell carcinoma in a dose-time dependent relationship.Extremely low concentration of ivermectin can promote the clone formation ability of tongue squamous cell carcinoma.2.Cisplatin exerted an inhibitory effect to SCC25 and CAL27 in a dose-time dependent relationship.Paclitaxel exerted an inhibitory effect to CAL27 in a dose-time dependent relationship,give play to the role of inhibition,for CAL27 dose-time dependencies play an inhibitory effect,while had no significant inhibitory effect on SCC25 within 72 hours.The results of the CCK8 quantitative calculation proved that ivermectin had a synergisitic effect with cisplatin/taxol.3.Ivermectin had anti-tumor effects in vivo experiments and strengthened the anti-tumor effect of paclitaxel at the same time with less obviously toxicity.4.Ivermectin inhibited the expression of KPNB1 in a dose dependent relationship and promoted the apoptosis of tongue squamous cell carcinoma.Conclusion:1.Ivermectin alone or synergistically with cisplatin and paclitaxel can inhibit the growth of tongue squamous cell carcinoma.2.Ivermectin can inhibit the migration of tongue squamous cell carcinoma.3.Ivermectin can enhance the anti-tumor effect of paclitaxel in vivo experiments,and can also exert anti-tumor effect when used alone,with less obviously toxicity to the main organs at the same time.4.Ivermectin can inhibit the expression of KPNB1 and promote the apoptosis of tumor cells.