sirolimus and Tongue-Neoplasms

Studies have shown the mammalian target of rapamycin (mTOR) and 70-kDa ribosomal protein S6 kinase (p70S6K) to be tumor suppressors in many cancers. These factors may have synergistic functions in tongue squamous cell carcinoma (TSCC), which is the most common malignant cancer in the oral region. We aimed to investigate the expression of the mTOR-p70S6K axis in TSCC patients and its biological function in TSCC cell lines.. Sixty-eight TSCC patients were included in this study, and their features, including age, gender, tumor differentiation, lymphatic metastasis, and clinical stage, were recorded. The expression of mTOR and p70S6K was detected by immunohistochemistry. Small interfering RNA constructs were delivered into TSCC cells to downregulate mTOR and p70S6K expression in vitro. After transfection, cell proliferation, migration or invasion, apoptosis, and chemoresistance assays were performed to examine cellular variations of biological function.. High expression of the mTOR-p70S6K axis was associated with higher tumor stage, lymph node metastasis, and poor tumor differentiation. Suppression of mTOR and p70S6K in TSCC cells resulted in the inhibition of cell proliferation, metastases, and chemoresistance. Inhibiting mTOR expression could inhibit p70S6K expression but not vice versa.. The high expression of mTOR and p70S6K is closely associated with malignant characterization of TSCC patients, and it could inhibit biological functions of TSCC cell lines. Taken together, the mTOR-p70S6K axis may serve as a potential therapeutic strategy for TSCC.

Topics: Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Humans; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Tongue Neoplasms; TOR Serine-Threonine Kinases

Recently, sirolimus was demonstrated to be effective in treating vascular lesions and lessening the frequency of bleeding and secondary iron deficiency anemia. We present a child with blue rubber bleb nevus syndrome who had prolonged history of iron deficiency anemia secondary to unrecognized gastrointestinal bleeding. Treatment with propranolol, omeprazole and iron had failed. After 2.5 months of sirolimus therapy (trough levels 1 to 5 ng/mL), his hemoglobin concentration improved into the normal range and remained stable. Vascular malformations on both the patient's tongue and in the fundus of his stomach shrank within 5 months of the initiation of sirolimus. In gastrointestinal involvement of blue rubber bleb nevus syndrome sirolimus was found to be effective even in the tongue's vascular lesions.

Topics: Abnormalities, Multiple; Anemia, Iron-Deficiency; Child; Consanguinity; Gastrointestinal Hemorrhage; Gastrointestinal Neoplasms; Heart Septal Defects, Atrial; Humans; Male; Neoplasms, Multiple Primary; Nevus, Blue; Oral Ulcer; Sirolimus; Skin Neoplasms; Tongue Neoplasms

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) frequently occurs in many human cancers and hampers their therapeutic use. A large body of evidence has demonstrated the pro-survival role of autophagy in many human cancers. However, whether autophagy is involved in the induction of erlotinib resistance in tongue squamous cell carcinoma (TSCC) remains unknown. In this report, we found that autophagy prior to or induced by erlotinib treatment plays an important role in erlotinib resistance in tongue cancer cells. Using LC3 transfection, we observed that autophagy is upregulated and further induced when treated with erlotinib. Moreover, we found that autophagy plays a cytoprotective role by MTT analysis of the cell viability in TSCCs when treated with rapamycin or hydroxychloroquine (HCQ) in combination with erlotinib. However, 3-methyladenine (3-MA) did not influence the autophagy. Then, through siRNA technology and WB, we found that erlotinib-induced autophagy is mediated by ATG5 but not Beclin1. Also, knockdown of ATG5 significantly decreased the erlotinib resistance and knockdown of Beclin1 did not affect the sensitivity to erlotinib in TSCCs. Taken together, this indicates the critical role of non-canonical autophagy in erlotinib resistance in TSCCs.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Autophagy-Related Protein 5; Beclin-1; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Hydroxychloroquine; RNA, Small Interfering; Sirolimus; Tongue Neoplasms; Up-Regulation

Lymphangiomas of the tongue are rare, and their treatment is problematic. A 10 year-old patient with tongue lymphangioma who was previously treated with surgery and propranolol with no response was treated with sirolimus in our department. We used sirolimus with a dose of 1.6 mg/m(2)/day. After 3 months of treatment, the mass had decreased by more than 60%. We continued the treatment for 1 year with a maximum response of 70% decrease in mass. Disease remained stable 6 months after stopping therapy, the latest time of follow-up. Sirolimus appears to be effective in lymphangioma but requires further study.

Topics: Adrenergic beta-Antagonists; Antibiotics, Antineoplastic; Child; Combined Modality Therapy; Humans; Lymphangioma; Male; Postoperative Complications; Propranolol; Sirolimus; Tongue Neoplasms; Treatment Outcome

Inhibition of mammalian target of rapamycin (mTOR) kinase enhances the radiosensitivity of some cancer cells. We investigated the effect of RAD001, an mTOR inhibitor, on irradiated oral cancer cell lines.. Clonogenic assays were performed to determine the radiosensitivity of SCC4 and SCC25 cells after treatment with RAD001. Target protein phosphorylation, apoptosis, and cell-cycle progression were assessed in SCC4 cells treated with RAD001 with and without ionizing radiation.. RAD001 increased the radiosensitivity of SCC4 cells without affecting cell death; it also inhibited phosphorylation of mTOR, S6, and factor 4E binding protein 1 and reduced the clonogenic survival of irradiated cancer cells. RAD001 combined with radiation increased G2 arrest by activating CHK1, which phosphorylates CDC25C at Ser216, thereby inhibiting CDC2-cyclin B 1 complex formation.. RAD001 enhances the radiosensitivity of SCC4 cells by inhibiting mTOR signaling and inducing G2 cell-cycle arrest through disruption of the G2 checkpoint.

Topics: Apoptosis; Blotting, Western; Carcinoma, Squamous Cell; Cell Cycle; Cell Cycle Checkpoints; Cell Proliferation; Everolimus; Humans; Immunosuppressive Agents; Phosphorylation; Radiation Tolerance; Radiation, Ionizing; Signal Transduction; Sirolimus; Tongue Neoplasms; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Autophagy is a catabolic process involving the degradation of cells' own unnecessary, injured, or aged proteins and recycling of degraded products to maintain hemostasis. Recently, studies indicated that autophagy plays a crucial role in cancer development. However, the role of autophagy in tongue squamous cell carcinoma (TSCC) has not been well documented. This study aims to assess the expression of autophagy-related protein and investigate its effect on TSCC.. Archival 50 TSCC samples were enrolled. Immunohistochemistry were performed to examine the expression of Beclin1 and LC3. Statistical analyses were carried out to assess the associations among clinicopathologic parameters. In vitro, cells were treated with rapamycin or 3-MA. Then, qPCR, western blot and immunofluorescence were performed to detect the expression of Beclin1 and LC3. Transmission electron microscopy was utilized to identify autophagsomes. For functional analysis, cell proliferation and cell cycle were evaluated with MTT assay and flow cytometer, respectively. At last, cell migration and invasion potentials were assessed by wound healing assay and transwell assay.. We confirmed that down-regulation of Beclin1 and LC3 is a frequent event in TSCC. Then, we demonstrated that decreased expression of Beclin1 was associated with T stage, clinical stage and differentiation. Furthermore, we showed that activation of autophagy by rapamycin suppressed proliferation, migration and invasion while inhibition of autophagy by 3-MA promoted proliferation, migration and invasion in TSCC cells.. Taken together, these data suggest that autophagy plays a pivotal role in the progression of TSCC.

Topics: Adenine; Antibiotics, Antineoplastic; Apoptosis Regulatory Proteins; Autophagy; Beclin-1; Carcinoma, Squamous Cell; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Progression; Female; Humans; Male; Membrane Proteins; Microtubule-Associated Proteins; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Phagosomes; Sirolimus; Tongue Neoplasms

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Prednisolone; Remission Induction; Sirolimus; Tongue Neoplasms; Treatment Failure; Treatment Outcome; Vincristine

FOXO3a, a well-known transcriptional regulator, controls a wide spectrum of biological processes. The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway inactivates FOXO3a via phosphorylation-induced nuclear exclusion and degradation. A loss or gain of FOXO3a activity has been correlated with efficiency of chemotherapies in various cancers including oral squamous cell carcinoma (OSCC). Therefore, in the current study, we have investigated the FOXO3a activity modulating and antitumor effects of rapamycin and cisplatin in OSCC cells. Cisplatin inhibited proliferation and induced apoptosis in a dose-dependent way in OSCC Tca8113 cells. Rapamycin alone had no effect on cell proliferation and apoptosis. Rapamycin downregulated the expression of S-phase kinase associated protein-2 (Skp2) and increased the FOXO3a protein stability but induced the upregulation of feedback Akt activation-mediated FOXO3a phosphorylation. Cisplatin decreased the phosphorylation of FOXO3a via Akt inhibition. Rapamycin combined with cisplatin as its feedback Akt activation inhibitor revealed the most dramatic FOXO3a nuclear localization and reactivation with the prevention of its feedback loop and exposed significant synergistic effects of decreased cell proliferation and increased apoptosis in vitro and decreased tumor size in vivo. Furthermore, the downstream effects of FOXO3a reactivation were found to be accumulation of p27 and Bim. In conclusion, rapamycin/cisplatin combination therapy boosts synergistic antitumor effects through the significant FOXO3a reactivation in OSCC cells. These results may represent a novel mechanism by which rapamycin/cisplatin combination therapy proves to be a potent molecular-targeted strategy for OSCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinase Inhibitor p27; Dose-Response Relationship, Drug; Drug Synergism; Forkhead Box Protein O3; Forkhead Transcription Factors; Humans; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Targeted Therapy; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; S-Phase Kinase-Associated Proteins; Sirolimus; Time Factors; Tongue Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

Post-transplant lymphoproliferative disease (PTLD) can occur in different sites, such as lymph nodes, allograft, and central nervous system. We report a 6-year-old girl with end-stage renal disease secondary to hypoplastic-dysplastic kidneys, who received a kidney transplant. Thirty months post transplant, she developed PTLD in the tongue, an area of muscular tissue only. At that time her peripheral blood Epstein-Barr viral (EBV) load was only 40 copies/10(5) lymphocytes, though the tumor was EB early RNA (EBER) positive. Immunosuppression was reduced with initial improvement in her symptoms. One month later, she returned with abdominal complaints and a contained cecal abscess. The excised cecal tissue revealed CD20 and EBER-positive lymphoid cells. At the same time, her peripheral blood EBV copy number rose to 400 copies/10(5) lymphocytes. She was successfully treated for the progressive PTLD by complete cessation of immunosuppression and a modified reduced-dose chemotherapy protocol plus rituximab. Partial immunosuppression was eventually re-introduced with sirolimus and prednisone. She remains in remission 60 months post transplant, and 30 months post PTLD, with serum creatinine value maintained at 1.3 mg/dL. Unusual localization of PTLD to areas in non-lymphoid tissue without regional lymphoid involvement may result in misleading low peripheral blood EBV viral loads.

Topics: Abscess; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cecum; Child; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Postoperative Complications; Prednisone; Rituximab; Sirolimus; Tongue Neoplasms; Viral Load