Ubenimex Reverses MDR in Gastric Cancer Cells by Activating Caspase-3-Mediated Apoptosis and Suppressing the Expression of Membrane Transport Proteins.

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.

Ubenimex induces autophagy inhibition and EMT suppression to overcome cisplatin resistance in GC cells by perturbing the CD13/EMP3/PI3K/AKT/NF-κB axis.

Cisplatin (CDDP)-based chemotherapy is a standard treatment for gastric cancer (GC). However, chemoresistance is a major obstacle for CDDP application. Exploring underlying mechanisms of CDDP resistance development in GC and selecting an effective strategy to overcome CDDP resistance remain a challenge. Here, we demonstrate that a transmembrane ectoenzyme, CD13, endows GC patients with insensitivity to CDDP and predicts an undesirable prognosis in GC patients with CDDP treatment. Similarly, CD13 expression is positively related with CDDP resistance in GC cells. A CD13 inhibitor, Ubenimex, reverses CDDP resistance and renders GC cells sensitivity to CDDP, for which CD13 reduction is essential, and epithelial membrane protein 3 (EMP3) is a putative target downstream of CD13. Furthermore, Ubenimex decreases EMP3 expression by boosting its CpG island hypermethylation for which CD13 down-regulation is required. In addition, EMP3 is a presumptive modifier by which CD13 exerts functions in the phosphoinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. Ubenimex inhibits the activation of the CD13/EMP3/PI3K/AKT/NF-κB pathway to overcome CDDP resistance in GC cells by suppressing autophagy and epithelial-mesenchymal transition (EMT). Therefore, CD13 is a potential indicator of CDDP resistance formation, and Ubenimex may serve as a potent candidate for reversing CDDP resistance in GC.

[Effect on blood pressure and microcirculation of nail fold in primary hypertension patients treated with acupuncture according to syndrome differentiation].

OBJECTIVE: To verify the efficacy of primary hypertension treated with acupuncture at acupoints selected according to syndrome differentiation and probe into the mechanism of acupuncture for primary hypertension. METHODS: One hundred and thirty-five cases of primary hypertension were randomized into an observation group (108 cases) and a control group (27 cases). In either group, Fengchi (GB 20), Quchi (LI 11), Zusanli (ST 36) and Sanyinjiao (SP 6) were selected conventionally. In observation group, on the basis of the acupoints selected above, the supplementary points were selected according to syndrome differentiation in Chinese medicine and the control group was selected main points only, once per day. After 15 days acupuncture, the efficacy and changes in microcirculation of nail fold were observed. RESULTS: The remarkable effective rate and the total effective rate were 29.6% (32/108) and 84.2% (91/108) in observation group respectively, which were superior to 18. 5% (5/27) and 70.4% (19/27) as compared with control group separately (both P < 0.05). After treatment, the microcirculation of nail fold was all improved in two groups, of which blood flow state integral, peripheral capillary loop state integral and the total integral were all improved obviously (all P < 0.05). The improvements in observation group were much more significant than those in control group (all P < 0.05). CONCLUSION: Acupuncture is effective significantly on primary hypertension and the point selection according to syndrome differentiation can improve the efficacy, which is probably relevant with the reduction in the peripheral vascular resistance due to the improvements of microcirculatory state in mechanism.

[Observation on therapeutic effect of Yongquan (KI 1) acupoint sticking therapy on infantile nasal obstruction].

OBJECTIVE: To search for an effective therapy for infantile nasal obstruction. METHODS: One hundred and twenty-five cases were randomly divided into an observation group of 62 cases and a control group of 63 cases. The observation group were treated with bilateral Yongquan (KI 1) application with Biyankang Tablet, once each night and the control group with dropping of 0.5% Ephedrine naristillae into the nose, one drop each nose each time, tid. The score for nasal obstruction were recorded before treatment and the third and the fifth days after treatment, and their therapeutic effects were assessed. RESULTS: After treatment, the symptom of nasal obstruction was significantly improved in the two groups (P < 0.01), with no significant difference between the two groups (P > 0.05). After treatment for 5 days, the effective rate was 76.8% in the observation group and 79.7% in the control group, their therapeutic effect being similar (P > 0.05). CONCLUSION: Yongquan (KI 1) acupoint sticking therapy is a safe and effective method for infantile nasal obstruction.