phenanthrenes and Squamous-Cell-Carcinoma-of-Head-and-Neck

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

Head and neck squamous cell carcinomas (HNSCCs) are the most common cancers of the head and neck, and their prevalence is rapidly increasing. HNSCCs present a clinical challenge because of their high recurrence rate, therapeutic resistance to radiation and chemotherapy drugs, and adverse effects. Hence, traditional Chinese herbal treatment may be advantageous to therapeutic strategies for HNSCCs. Danshen (

Topics: Animals; Apoptosis; Cell Proliferation; Drugs, Chinese Herbal; Head and Neck Neoplasms; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phenanthrenes; Salvia miltiorrhiza; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; 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