phenanthrenes and Mouth-Neoplasms

Biological and prognostic roles of programmed death ligand 1 (PD-L1) remain unclear in oral squamous cell carcinoma (OSCC). Moreover, the pivotal role of tumor microenvironmental interferon-gamma (IFN-γ) in host responses to malignant cells, oral cancer growth, and PD-L1 expression has not been adequately studied. Thus, PD-L1 expression in 130 OSCC samples was analyzed using immunohistochemistry, which was found significantly overexpressed at the tumor site (P <  .01). We further analyzed the effects of IFN-γ on OSCC cell proliferation using enzyme-linked immunosorbent assays and found that IFN-γ drives PD-L1 expression in OSCC cells in a dose-dependent manner. Triptolide (TPL), a bioactive compound isolated from Tripterygium wilfordii, exhibits anti-inflammatory and antitumor activities. To investigate whether the antitumor effect of TPL involves the suppression of PD-L1 expression, we treated OSCC cells in vitro and a patient-derived tumor xenograft (PDTX) model with TPL. TPL suppressed PD-L1 expression in the PDTX model, inhibiting tumor growth, and in OSCC cells in an IFN-γ-modulated microenvironment. We concluded that TPL inhibits tumor growth in oral cancer and downregulates PD-L1 expression in oral cancer cells in vitro. Our results provide evidence for the clinical development of PD-L1-targeted therapy for OSCC.

Topics: Adult; Aged; Aged, 80 and over; Animals; B7-H1 Antigen; Cell Line, Tumor; Cell Proliferation; Diterpenes; Down-Regulation; Epoxy Compounds; Female; Humans; Immune Checkpoint Inhibitors; Interferon-gamma; Janus Kinase 2; Male; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mouth Neoplasms; Phenanthrenes; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; STAT1 Transcription Factor; Tumor Burden; Tumor Microenvironment; Xenograft Model Antitumor Assays

Cisplatin alone or in combination with 5FU (5-fluorouracil) and docetaxel (TPF) are common regimen chemotherapeutics for treatment of advanced oral squamous cell carcinoma (OSCC). Despite the initial positive response, several patients experience relapse due to chemoresistance. The potential role of Bcl-2 antiapoptotic members in acquired chemoresistance is yet to be explored. To address this, we designed two different relevant OSCC chemoresistant models: (i) acquired chemoresistant cells, where OSCC lines were treated with conventional chemotherapy for a prolonged period to develop chemoresistance, and (ii) chemoresistant patient-derived cells, where primary cells were established from tumor of neoadjuvant-treated OSCC patients who do not respond to TPF. Among all Bcl-2 antiapoptotic members, Mcl-1 expression (but not Bcl-2 or Bcl-xL) was found to be upregulated in both chemoresistant OSCC lines and chemoresistant tumors when compared with their respective sensitive counterparts. Irrespective of all three chemotherapy drugs, Mcl-1 expression was elevated in OSCC cells that are resistant to either cisplatin or 5FU or docetaxel. In chemoresistant OSCC, Mcl-1 mRNA was upregulated by signal transducer and activator of transcription 3 (STAT3) activation, and the protein was stabilized by AKT-mediated glycogen synthase kinase 3 beta (GSK3β) inactivation. Genetic (siRNA) or pharmacological (Triptolide, a transcriptional repressor of Mcl-1) inhibition of Mcl-1 induces drug-mediated cell death in chemoresistant OSCC. In patient-derived xenograft model of advanced stage and chemoresistant OSCC tumor, Triptolide restores cisplatin-mediated cell death and facilitates significant reduction of tumor burdens. Overall, our data suggest Mcl-1 dependency of chemoresistant OSCC. A combination regimen of Mcl-1 inhibitor with conventional chemotherapy deserves further clinical investigation in advanced OSCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cisplatin; Diterpenes; Drug Resistance, Neoplasm; Epoxy Compounds; Fluorouracil; Glycogen Synthase Kinase 3 beta; Humans; Male; Mice; Mouth Neoplasms; Myeloid Cell Leukemia Sequence 1 Protein; Phenanthrenes; Proto-Oncogene Proteins c-akt; Squamous Cell Carcinoma of Head and Neck; STAT3 Transcription Factor; Taxoids

Aberrant expression of decoy receptor 3 (DcR3) is considered to be a diagnostic and therapeutic target for human cancers. The aim of this study was to assess DcR3 as a target of the anticancer effects of triptolide (TPL) in preclinical patient-derived tumor xenograft (PDTX) models of oral squamous cell carcinoma (OSCC).. The expression of DcR3 was evaluated through immunohistochemistry, and correlations were examined using clinical variables. The effects of TPL on the expression of DcR3 and cell proliferation were investigated in OSCC cell lines and in PDTX models.. DcR3 overexpression was associated with overall survival and tumor size. TPL significantly decreased tumor growth. Moreover, TPL inhibited the expression of metastasis-associated protein 1 (MTA1), a transcription factor for DcR3 in vivo, in vitro, and in PDTX models.. TPL appeared to exert anticancer effects by repressing DcR3 and MTA1 in vitro, in vivo, and in PDTX models.

Topics: Animals; Antineoplastic Agents, Alkylating; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Proliferation; Diterpenes; Down-Regulation; Epoxy Compounds; Heterografts; Humans; Immunohistochemistry; Mice; Mice, Inbred NOD; Mouth Neoplasms; Phenanthrenes; Receptors, Tumor Necrosis Factor, Member 6b; Xenograft Model Antitumor Assays

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Cell Cycle; Cell Division; Cell Line, Tumor; Cell Proliferation; Diterpenes; Epoxy Compounds; Humans; Mouth Neoplasms; Phenanthrenes; PTEN Phosphohydrolase; RNA, Messenger; Time Factors

In a previous study, we demonstrated that cyclooxygenase-2 (COX-2) is overexpressed in Korean patients having oral cancer. The goal of this study was to study whether KO-202125 (KO), a sauristolactam derivative in KB human oral squamous carcinoma cells, inhibits the activity of COX-2 enzyme and induces apoptotic cell death. In this study, it was shown that KO inhibited COX-2 mRNA and protein and its catalytic activity (prostaglandin E2), but not COX-1. The antiproliferative effect of KO on KB cells was also examined. The results showed that KO significantly decreased the number of viable cells and showed morphological changes in a concentration-dependent manner. The decrease in cell number was associated with apoptotic cell death evidenced by cleaved poly ADP ribose polymerase (PARP), nuclear fragmentation, sub-G1 population and annexin V positivity. Interestingly, KO is more potent than celecoxib, which is a well-known selective COX-2 inhibitor, although more studies are needed to prove it. Altogether, these results show that KO can act as a potent antioral cancer drug candidate by regulating COX-2 activity.

Topics: Alkaloids; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Celecoxib; Cell Proliferation; Cell Survival; Cyclooxygenase 2; Down-Regulation; Drug Evaluation, Preclinical; Gene Expression Regulation, Enzymologic; Humans; Isoindoles; KB Cells; Lactams; Mouth Neoplasms; Phenanthrenes; Pyrazoles; Sulfonamides

Triptolide (TPL), a diterpenoid triepoxide purified from the Chinese herb Tripterygium wilfordii Hook F, has been reported to potentiate the anti-tumor effect in various cancer cells. However, the effect of TPL on oral cancers is not yet evaluated. Herein we first demonstrate that TPL induces prominent growth inhibition and apoptosis in two oral cancer cell lines, SCC25 and OEC-M1 and in KB cells. Our results indicate that TPL induces a dose-dependent apoptosis of these cells at nanomolar concentration. Apoptosis signalings are both activated through time upon TPL treatment detected by elevated caspase-3, 8, 9 activities. In xenograft tumor mouse model, TPL injection successfully inhibits the tumor growth via apoptosis induction which was demonstrated by TUNEL assay. These results demonstrate that TPL exerts anti-tumor effect on oral cancer and KB cells and suggest further the potential of TPL combining with other chemotherapeutic agents or radiotherapy for advanced oral cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Disease Models, Animal; Diterpenes; Drug Screening Assays, Antitumor; Epoxy Compounds; Humans; KB Cells; Mice; Mice, Inbred NOD; Mice, SCID; Mouth Neoplasms; Phenanthrenes

Phenanthrene (Phe) and to a lesser degree 1,4-dimethylnaphthalene (DMeN) were each found to retard the development of epidermoid carcinomas in hamster buccal pouch induced by the thrice weekly application of a 0.5 per cent solution of 7,12-dimethylbenz[a]anthracene (DMBA) in heavy mineral oil.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Benz(a)Anthracenes; Cheek; Cricetinae; Female; Male; Mesocricetus; Mouth Neoplasms; Naphthalenes; Neoplasms, Experimental; Phenanthrenes; Time Factors

Topics: Antineoplastic Agents; Carcinoma; Cell Line; Cells, Cultured; Humans; In Vitro Techniques; Indolizines; Isoquinolines; Mouth Neoplasms; Neoplasms, Experimental; Phenanthrenes; Piperidines

Topics: Animals; Carcinoma; Cattle; Cell Line; Chromatography, Thin Layer; Culture Media; Humans; Infrared Rays; Lipids; Mouth Neoplasms; Phenanthrenes; Spectrophotometry; Thymus Gland; Tissue Extracts; Ultraviolet Rays