Abstract
Gastric cancer (GC) is one of the most malignant tumors, accounting for 10% of deaths caused by all cancers. Chemotherapy is often necessary for treatment of GC; the FOLFOX regimen is extensively applied. However, multidrug resistance (MDR) of GC cells prevents wider application of this treatment. Ubenimex, an inhibitor of CD13, is used as an immune adjuvant to treat hematological malignancies. Here, we demonstrate that CD13 expression positively correlates with MDR development in GC cells. Moreover, Ubenimex reverses the MDR of SGC7901/X and MKN45/X cells and enhances their sensitivity to FOLFOX, in part by decreasing CD13 expression, which is accompanied by downregulation of Bcl-xl, Bcl-2, and survivin expression; increased expression of Bax; and activation of the caspase-3-mediated apoptotic cascade. In addition, Ubenimex downregulates expression of membrane transport proteins, such as P-gp and MRP1, by inhibiting phosphorylation in the PI3K/AKT/mTOR pathway to increase intracellular accumulations of 5-fluorouracil and oxaliplatin, a process for which downregulation of CD13 expression is essential. Therefore, the present results reveal a previously uncharacterized function of CD13 in promoting MDR development in GC cells and suggest that Ubenimex is a candidate for reversing the MDR of GC cells.
Highlights
Gastric cancer (GC) is the fourth most serious cancer worldwide, and the second greatest cause of cancer-related death, next to lung cancer [1]
Rabbit anti-human antibodies against P-gp, multidrug resistance-associated protein 1 (MRP1), ABCG2, lung resistance protein (LRP), PI3K(P85), p-PI3K(p-P85), AKT, p-AKT, GSK-3β, pGSK-3β, JNK, p-JNK, mTOR, p-mTOR, and PE-conjugated cytochrome c (Cyto-C) mAb were obtained from Cell Signaling Technology (Danvers, MA)
Immunohistochemistry results demonstrated that various grades of expression of CD13 were present in tissue samples from the 120 GC patients (Table 1)
Summary
Gastric cancer (GC) is the fourth most serious cancer worldwide, and the second greatest cause of cancer-related death, next to lung cancer [1]. Surgery is the main treatment for GC, but late diagnoses are associated with advanced cancers, which tend to be metastatic after resection [2]. Chemotherapy, often utilized to treat GC, offers better outcomes than surgery alone [3]. The FOLFOX regimen, comprised of 5-fluorouracil, oxaliplatin, and leucovorin, is often the primary choice of chemotherapy for GC due to its mild toxicity and better tolerance; it improves the median survival of patients, especially those with advanced GC [4,5,6]. Application of the FOLFOX regimen for GC patients is hindered by multidrug resistance (MDR), for which tumor cells show resistance to a specific drug, and are resistant to other drugs with different structures and mechanisms [7]
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