| Gefitinib and icotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, have been widely used to treat non-small cell lung cancer in clinical. There are no significant difference of the both Progression-Free-Survival (PFS), so they are able to effectively improve the overall survival of cancer patients. However, several side effects are usually appearance using the two molecular targeting medicines, and the gastrointestinal toxicity are most serious. The gastrointestinal adverse effect induced diarrhea is detrimental to patient quality of life, it also limit the ability to deliver full chemotherapeutic doses, that will influence the advances of chemotherapy, and this even be threatening the patient life. There are definite mechanisms of the two molecular targeting chemotherapeutic agents, but the mechanism of diarrhea is not clearly. So it is very important to investigate the pathophysiologic mechanisms for this kind of diarrhea for improving the quality of patient life and advance of chemotherapy.In the first part, we summarized the adverse effects of chemotherapy drugs and the effects of Endoplasmic reticulum stress (ER Stress) in many diseases. ER stress involved in the occurrence and development of many diseases, so it could induce the generation of the side effects of chemotherapy drugs, and it seems that this kind of diarrhea can be treated by targeting ER stress signaling pathway.In the second part, we compared the adverse cases of two groups treated with gefitini 250 mg one day and icotinib 125 mg three times a day respectively. And we found that gefitinib appears to have higher diarrhea cases than icotinib at each approved dose. Under this interesting phenomenon, we examined the effect of gefitinib and icotinib in vitro with IEC-6 cell lines, and verified in the Caco-2 cells. The result showed that Gefitinib exerted more cytotoxicity than icotinib to inhibit proliferation and to induce apoptosis of IEC-6 cells. At same time, the apoptosis related proteins (cleaved PARP and cleaved Caspase-3) increased with 24h treatment of gefitinib but not happen in icotinib. And gefitinib inhibited the expression of the cycle-related proteins like Cyclin D1 and p27, arrested more cells in G0/G1 phase. In addition, compared with icotinib, gefitinib significantly suppressed levels of cell adhesion molecules while increased expression of proinfalmmatory cytokines. Finally, gefitinib triggered endoplasmic reticulum (ER) stress response, characterized by stimulation of PERK pathway and IRE 1 pathway; thus to result in ER-mediated cell death. However, these changes induced by icotinib was mild.In the third part, we further investigated the mechanism that berberine hydrochloride inhibited the diarrhea induced by gefitinib in vivo and vitro. The results showed that treating with berberine hydrochloride could significantly decrease the weight loss, diarrhea and the increasing of colon pathology score. And berberine hydrochloride suppressed apoptosis, expression of proinfalmmatory cytokines interleukin (IL)-6 and IL-25 in vitro. Importantly, it can suppress the expression of the mRNA and protein levels in ER stress signaling pathways.In summary, gefitinib induced more diarrhea cases than icotinib by increasing the expression of ER stress related proteins. However, berberine hydrochloride could treat diarrhea of gefitinib by declining the apoptosis due to the rise of ER stress. Thus, these findings could provide a new idea for prevention and cure such diarrhea in clinical. |
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