benzofurans and Head-and-Neck-Neoplasms

In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed.. Carzelesin was used as second- or third-line chemotherapy in patients with breast, ovarian, head and neck cancer and non-Hodgkin's lymphoma, and as first-line chemotherapy in patients with colorectal and gastric cancer and melanoma. The drug was given as a bolus infusion at a 4-weekly dose of 150 microg/m2. A total of 140 patients were entered and a total of 285 courses were administered.. In general, the compound was well tolerated. Myelotoxicity was the most common toxicity. Grade 3 and 4 leukopenia was observed in 18.6% of the courses, neutropenia in 20.3%, thrombocytopenia in 16.2% and anemia in 8.7%. Double nadirs were seen in a total of 41 courses for neutrophils, in 40 for leukocytes and in 3 for platelets. Non-hematological toxicity was very mild. Only one partial response in a patient with melanoma was seen.. At this dose and schedule carzelesin did not yield activity in the types of tumors studied.

Topics: Adult; Aged; Antineoplastic Agents; Benzofurans; Breast Neoplasms; Colorectal Neoplasms; Duocarmycins; Female; Head and Neck Neoplasms; Humans; Indoles; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melanoma; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Prodrugs; Stomach Neoplasms

Salvianolic acid B (SalB) was demonstrated to be a promising chemopreventive agent for head and neck squamous cell carcinoma (HNSCC) in the previous studies by our and other research institution, but the properties like low efficacy, poor systemic delivery, and low bioavailability has hampered its clinical applications. To continue our research program focused on the use of natural compounds on cancer chemoprevention, we propose a first example of phospholipid complex loaded nanoparticles (PLC-NPs) encapsulating SalB as a potential carrier for intervention of HNSCC (HN13, HN30) cells and precancer Leuk1 cells in this study. Qualitative and quantitive studies of cellular uptake showed that intracellular accumulation of SalB was significantly higher when HN13, HN30 and Leuk1 cells were incubated with SalB-PLC-NPs complex (nano-SalB) as against free-SalB. Cell viability assay revealed that the cell growth of HN13 and HN30 cells was significantly inhibited of 56.1% and 29.3%, respectively, for nano-SalB compared to an equivalent amount of free-SalB (P<0.001). Moreover, cell cycle and apoptosis assay showed that a clear trend of cell cycle arrest and induction of apoptosis was also observed within the HNSCC cells treated with nano-SalB. Collectively, this study demonstrated that nano-SalB was significantly more potent had an anticancer effect against HNSCC cells, which serves as the first step toward establishing SalB nano-formulations as promising cancer chemopreventive agents. The current study could pave a new way for the development of drugs that target HNSCC in the future.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Carcinoma, Squamous Cell; Cell Cycle; Cell Proliferation; Drugs, Chinese Herbal; Head and Neck Neoplasms; Humans; Nanoparticles; Precancerous Conditions; Tumor Cells, Cultured

Head and neck squamous cell carcinoma (HNSCC) development is closely associated with inflammation. Cyclooxygenase-2 (COX-2) is an important mediator of inflammation. Therefore, celecoxib, a selective inhibitor of COX-2, was hailed as a promising chemopreventive agent for HNSCC. Dose-dependent cardiac toxicity limits long-term use of celecoxib, but it seems likely that this may be diminished by lowering its dose. We found that salvianolic acid B (Sal-B), isolated from Salvia miltiorrhiza Bge, can effectively suppress COX-2 expression and induce apoptosis in a variety of cancer cell lines. In this study, we report that combination of Sal-B with low-dose celecoxib results in a more pronounced anticancer effect in HNSCC than either agent alone. The combination effects were assessed in four HNSCC cell lines (JHU-06, JHU-011, JHU-013, and JHU-022) by evaluating cell viability, proliferation, and tumor xenograft growth. Cell viability and proliferation were significantly inhibited by both the combined and single-agent treatments. However, the combination treatment significantly enhanced anticancer efficacy in JHU-013 and JHU-022 cell lines compared with the single treatment regimens. A half-dose of daily Sal-B (40 mg/kg/d) and celecoxib (2.5 mg/kg/d) significantly inhibited JHU-013 xenograft growth relative to mice treated with a full dose of Sal-B or celecoxib alone. The combination was associated with profound inhibition of COX-2 and enhanced induction of apoptosis. Taken together, these results strongly suggest that combination of Sal-B, a multifunctional anticancer agent, with low-dose celecoxib holds potential as a new preventive strategy in targeting inflammatory-associated tumor development.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzofurans; Carcinoma, Squamous Cell; Celecoxib; Cell Division; Cell Line, Tumor; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Synergism; Head and Neck Neoplasms; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Nude; Pyrazoles; Salvia miltiorrhiza; Sulfonamides; Xenograft Model Antitumor Assays

Overexpression of cyclooxygenase-2 (COX-2) in oral mucosa has been associated with increased risk of head and neck squamous cell carcinoma (HNSCC). Celecoxib is a nonsteroidal anti-inflammatory drug, which inhibits COX-2 but not COX-1. This selective COX-2 inhibitor holds promise as a cancer preventive agent. Concerns about cardiotoxicity of celecoxib, limits its use in long-term chemoprevention and therapy. Salvianolic acid B (Sal-B) is a leading bioactive component of Salvia miltiorrhiza Bge, which is used for treating neoplastic and chronic inflammatory diseases in China. The purpose of this study was to investigate the mechanisms by which Sal-B inhibits HNSCC growth. Sal-B was isolated from S. miltiorrhiza Bge by solvent extraction followed by 2 chromatographic steps. Pharmacological activity of Sal-B was assessed in HNSCC and other cell lines by estimating COX-2 expression, cell viability and caspase-dependent apoptosis. Sal-B inhibited growth of HNSCC JHU-022 and JHU-013 cells with IC(50) of 18 and 50 microM, respectively. Nude mice with HNSCC solid tumor xenografts were treated with Sal-B (80 mg/kg/day) or celecoxib (5 mg/kg/day) for 25 days to investigate in vivo effects of the COX-2 inhibitors. Tumor volumes in Sal-B treated group were significantly lower than those in celecoxib treated or untreated control groups (p < 0.05). Sal-B inhibited COX-2 expression in cultured HNSCC cells and in HNSCC cells isolated from tumor xenografts. Sal-B also caused dose-dependent inhibition of prostaglandin E(2) synthesis, either with or without lipopolysaccharide stimulation. Taken together, Sal-B shows promise as a COX-2 targeted anticancer agent for HNSCC prevention and treatment.

Topics: Animals; Apoptosis; Benzofurans; Blotting, Western; Carcinoma, Squamous Cell; Caspases; Cells, Cultured; Colony-Forming Units Assay; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drugs, Chinese Herbal; Female; Flow Cytometry; Head and Neck Neoplasms; Humans; In Vitro Techniques; Keratinocytes; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salvia miltiorrhiza; Survival Rate; Transplantation, Heterologous