leupeptins and Hypopharyngeal-Neoplasms

Multidrug resistance (MDR) is a major impediment to cancer therapy. MG‑132 has been identified to be effective against MDR in several types of cancer. However, the mechanism of MG‑132 in head and neck squamous cell carcinomas remains unknown. Based on our previous study, the present detected P‑gp and P‑gp expression in hypopharyngeal carcinoma FaDu cells, revealing that their expression was lower than that observed in the MDR cell line FaDu/T. To reverse the MDR of FaDu/T cells, the present study introduced MG‑132 and demonstrated that the high expression of P‑gp/P‑gp in FaDu/T cells was attenuated in a time‑dependent manner. MG‑132 also strengthened the sensitivity of FaDu/T cells to multidrugs. c‑Jun N‑terminal kinase (JNK) activation was further observed in FaDu/T cells. However, P‑gp/P‑gp did not decrease when FaDu/T cells were pretreated with SP600125. These results indicated that MG‑132 reversed the MDR of hypopharyngeal carcinoma by downregulating P‑gp/P‑gp, and the underlying mechanism may be associated with the activation the of the JNK signaling pathway.

Topics: Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Hypopharyngeal Neoplasms; Leupeptins; MAP Kinase Signaling System; Paclitaxel; T-Lymphocytes

In order to reverse the malignant characteristics of hypopharyngeal cancer, the proteasome inhibitor MG132 was introduced into FaDu/T cells and the mechanisms underlying its effects were investigated. The multi-drug resistance (MDR) sensitivities of FaDu/T and FaDu/T-MG132 cancer cells to several chemotherapeutics were investigated by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT) assay. Apoptosis was measured by staining cells with Annexin V and propidium iodide (PI) double staining. Reverse transcription-polymerase chain reaction and western blot analysis were conducted to detect mRNA and corresponding protein levels of the MDR- and apoptosis-related genes P-glycoprotein (P-gp), caspase-3, Bcl-2 and Bax. The nuclear protein of nuclear factor κ-light-chain-enhancer of activated B cells. (NF-κB) and p53 were also investigated via western blot analysis. Compared with FaDu/T cells, the drug resistance of FaDu/T + MG132 cells to cisplatin (DDP), 5-fluorouracil (5-FU), doxorubicin (Dox) and vincristine (VCR) decreased. With increased expression of caspase-3 and Bax and decreased expression of Bcl-2, the anti-apoptotic ability markedly decreased in FaDu/T + MG132 cells. P-gp and NF-κB significantly decreased; however, p53 increased in FaDu/T + MG132 cells. These results suggested that the proteasome inhibitor MG132 reversed the malignant characteristics of FaDu/T by enhancing apoptosis and inhibiting P-gp. MG132 was also able to inhibit the nuclear translocation of NF-κB and increase the expression of p53.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Hypopharyngeal Neoplasms; Inhibitory Concentration 50; Leupeptins; NF-kappa B; Paclitaxel; Proteasome Inhibitors; Protein Transport; Tumor Suppressor Protein p53