| Background and ObjectivesChemotherapy is an important method for the treatment of malignancy, but the resistance which is occurred in a long term use of drug and the side effects always lead to failure of treatment. Thus, the agent that can enhance the sensibility of tumor to chemotherapy drug and decrease the side effects is very important.Phorbol ester,a kind of ester which is formed by14alkanes acid and phorbol.It can activate the signal pathways which can lead to cell proliferation and differentiation. TPA (12-O-tetradecanoyphorbol-13-acetate) has the highest activity among the phorbol eaters. According to the literatures, it can increase the sensitivity of tumor cells to cisplatin, such as human lung cancer cells, ovarian cancer cells, cervical cancer cells, leukemia cells and so on. Besides, TPA can also increase the sensitivity of prostatic cancer and osteosarcoma cells to paclitaxel. The study now is aimed at investigating the sensibilization effect of TPA on TP regimen. In addition, the side effects of TP regimen is also an obstacle in cancer treatment, so this study also examine whether TPA can antagonize the side effects of TP regimen at the mean time.In this study, using A549, SPC-A-1cell lines and Kunming mouse as research objects, we investigated the anti-tumor effects of phorbol ester on TP regimen. MethodsA549and SPC-A-1cell lines were maintained in RPMI-1640medium containing10%of fetal bovine serum(FBS),100U/mL penicillin,100U/mL streptomycin in a humidified atmosphere with5%CO2at37’C. Male mice were maintained in a temperature22±2℃and relative humidity55±15%-controlled room with a12h light and dark cycle, also, animals were allowed food and tap water ad libitum. Mice were maintained in these facilities for5days before the experiment.The cell proliferation was observed by MTT. Cells were treated by TPA、 cisplatin、paclitaxel respectively or TPA in combination with TP regimen. Acute toxicity test was taken to observe whether TPA can antagonize the side effects induced by TP regimen. Using the automatic biochemistry analyzer and HE staining, we tested the serum level of BUN and CRE, and the pathological damage of kidney tissue to make sure if TPA can protect the side effects of TP regimen. According to our results, H22cell was transplanted to mice to observe the efficacy and toxicity effect of TPA to TP regimen by testing the tumor inhibition rate and the serum level of BUN and CRE. At last, using the test kits we tested several indicators of oxidative stress, such as MDA, GSH, and SOD.ResultsOur results have showen that TPA in1ng/ml has a good sensibilization to cisplatin, but not to paclitaxel. TPA can decrease the IC50of cisplatin significantly. According to our previous results, the reason TPA sensitives cisplatin is that TPA activities the Na, K,-ATPase so that the intracellular accumulation of cisplatin is increased. Besides, the results of the acute toxicity experiment have showen that TPA can obviously reduce the mortality of animals induced by TP regimen. TPA alone had no effect on animals. The mortality of TP group was86.67%, however, TPA in combination with TP group was26.67%. Then we tested the antagonism effect of TPA to the dose-limiting toxicities of cisplatin and paclitaxel. In the nephrotoxicity induced by cisplatin, TPA can obviously decrease the serum level of BUN and CRE. Besides, the damage of kidney was restored. But TPA has no effect to myelosuppression induced by paclitaxel.Next, in the mouse that bearing tumors, TPA can not only reduce the increase of BUN and CRE induced by TP regimen, but also decrease the weight of tumors. Besides, TPA can significantly reduce the oxidative stress induced by cisplatin, namely, the level of MDA, SOD and ROS in kidney.ConclusionsThe results suggest that TPA can enhance the sensitivity of lung cancer cells to TP regimen in vitro, increase the antitumour efficiency and reduce the nephrotoxicity in mice. |
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