ABSTRACT
Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with oral cancer. Proton pump inhibitors (PPIs), essentially H+-K+-ATPase inhibitors which are currently used in the treatment of acid related diseases, have demonstrated promising antitumor and chemo-sensitizing efficacy. The main purpose of the present study was to investigate whether pantoprazole (PPZ, one of PPIs) could increase the sensitivity of chemoresistant oral epidermoid carcinoma cells (KB/V) to vincristine (VCR) and elucidate the underlying action mechanism. Results showed that combination treatment of PPZ and VCR synergistically inhibited the proliferation of KB/V cells in vitro and in vivo. Furthermore, administration of PPZ and VCR not only induce apoptosis and G2/M phase arrest in KB/V cells but also suppress the migration and invasion of KB/V cells. The mechanism underlying synergistic anti-tumor effect of PPZ and VCR was related to the inhibition of the function and expression of P-glycoprotein (P-gp) and the down-regulation of EGFR/MAPK and PI3K/Akt/mTOR signaling pathways in KB/V cells. Additionally, we observed that PPZ treatment induced an increase in lysosomal pH and inhibited the activity of lysosomal enzyme acid phosphatase in KB/V cells, which could functionally reduce the sequestration of VCR in lysosomes and sensitized KB/V cells to VCR. In conclusion, our study demonstrated that PPZ could be included in new combined therapy of human oral cancer (especially on VCR-resistant therapy) together with VCR.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Drug Resistance, Neoplasm/drug effects , Mouth Neoplasms/drug therapy , Pantoprazole/pharmacology , Vincristine/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Apoptosis/drug effects , Carcinoma, Squamous Cell/metabolism , Cell Line , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Humans , KB Cells , Mice , Mice, Inbred BALB C , Mouth Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolismABSTRACT
Herbaceous peony (Paeonia lactiflora Pall.) is an excellent ornamental plant, which is usually stressed by summer high temperatures, but little is known about its relevant measures. In this study, the effects of trehalose on alleviating high temperature-induced damage in P. lactiflora were examined. High temperature stress in P. lactiflora increased production of reactive oxygen species (ROS), including superoxide anion free radical (O2·-) and hydrogen peroxide (H2O2), enhanced both malondialdehyde (MDA) content and relative electrical conductivity (REC), decreased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, inhibited photosynthesis, and destroyed cell structure. However, exogenous trehalose effectively alleviated its high temperature-induced damage. Trehalose decreased O2·- and H2O2 accumulation, MDA content, and REC, increased the activities of antioxidant enzymes, enhanced photosynthesis, improved cell structure, and made chloroplasts rounder. Additionally, trehalose induced high temperature-tolerant-related gene expressions to different degrees. These results indicated that trehalose decreased the deleterious effect of high temperature stress on P. lactiflora growth by enhancing antioxidant systems, activating photosynthesis, and protecting cell structure. These findings indicate the potential application of trehalose for managing high temperatures in P. lactiflora cultivation.
