phenanthrenes and Carcinoma--Squamous-Cell

Some pharmacologic properties of nine antitumor agents from higher plants are described. The agents are vincristine, vinblastine the epiodophyllotoxin derivatives VM-26 and VP-16-213, maytansine, bruceantin, thalicarpine, camptothecin, and lapachol. When sufficient information is available, the agents are discussed with regard to their antitumor activity, mechanism of action, pharmacologic disposition, structure-activity relationships, and toxicity.

Topics: Animals; Antineoplastic Agents, Phytogenic; Aporphines; Camptothecin; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Etoposide; Humans; Leukemia L1210; Leukemia, Experimental; Leukemia, Lymphoid; Maytansine; Melanoma; Naphthoquinones; Nasopharyngeal Neoplasms; Neoplasms; Neoplasms, Experimental; Phenanthrenes; Structure-Activity Relationship; Teniposide; Vinblastine; Vincristine

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Hydrocarbons; Ketones; Methylcholanthrene; Mice; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sarcoma, Experimental; Skin Neoplasms; Steroids

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

Two new phenanthrenes, (1

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Humans; Hypopharyngeal Neoplasms; Magnetic Resonance Spectroscopy; Molecular Structure; Orchidaceae; Phenanthrenes; Plant Extracts; Structure-Activity Relationship

Cryptotanshinone, a natural compound isolated from the roots of Salvia miltiorrhiza Bge (Danshen), has been found to induce cancer cells apoptosis and impair cell migration and invasion in various malignancies, but its antiproliferation and chemosensitization effects of Cryptotanshinone on tongue squamous cell carcinoma(TSCC)still remain fully elucidated. In this study, the effects of Cryptotanshinone on the proliferation, apoptosis and cell cycle of human TSCC cells, including CAL 27 and SCC 9 cells, were measured. The results demonstrated that Cryptotanshinone dose-dependently inhibited cell migration and proliferation, and induced apoptosis in TSCC cells. Mechanistic study revealed that Cryptotanshinone suppressed the expression of p-STAT3, Bcl-2, CDK2, Snail and MMP2, and induced the expression of E-cadherin, P53, P21 and β-catenin. Furthermore, we found that the combination treatment of Cryptotanshinone and paclitaxel more effectively inhibited TSCC cell proliferation and migration, and induced apoptosis via the inhibition of STAT3 signaling pathway. In brief, we provided the new evidence that Cryptotanshinone could enhance the efficacy of paclitaxel on TSCC cells in vitro and demonstrated that STAT3 signaling pathway played an important role in Cryptotanshinone-induced anticancer effects in human TSCC.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Checkpoints; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Humans; Janus Kinases; Models, Biological; Neoplasm Invasiveness; Paclitaxel; Phenanthrenes; Signal Transduction; STAT3 Transcription Factor; Tongue Neoplasms

Advanced oral cancer is a major public health concern because of a lack of effective prevention and treatment. Triptolide (TPL), a diterpenoid triepoxide derived from the Chinese herb Tripterygium wilfordii, has been demonstrated to possess strong anticancer properties. In this study, we investigated whether TPL exerts anticancer effects on the tumor microenvironment of head and neck squamous cell carcinoma (HNSCC).. Human macrophage-like U937 cells were co-inoculated with oral cancer SAS cells in a noncontact transwell coculture system. Cytokine expression was detected using ELISA, and cell proliferation was detected using methylene blue. RNA levels were detected using qPCR. Protein levels were detected using Western blot analysis. In vivo experiments involved using xenografted NOD/SCID mice.. Our results demonstrated that TPL inhibited the growth of SAS cells co-inoculated with U937 cells in vitro and in vivo. TPL inhibited the invasion, migration ability, and angiogenesis of SAS cells co-inoculated with U937 cells. Expression of cytokines IL-6, IL-8, and TNF-α was induced by co-inoculation, but TPL repressed their expression.. TPL suppressed the expression of cytokines IL-6, IL-8, and TNF-α, as well as tumor growth, invasion, migration, and angiogenesis in the co-inoculation of human tongue cancer cells with macrophage-like U937 cells.. TPL is a potential candidate among novel chemotherapeutic agents or adjuvants for modulating tumor-associated macrophages in a tumor microenvironment of HNSCC.

Topics: Animals; Antineoplastic Agents, Alkylating; Blotting, Western; Carcinoma, Squamous Cell; Cell Movement; Cell Proliferation; Coculture Techniques; Cytokines; Diterpenes; Enzyme-Linked Immunosorbent Assay; Epoxy Compounds; Head and Neck Neoplasms; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neovascularization, Pathologic; Phenanthrenes; Polymerase Chain Reaction; Tumor Microenvironment; U937 Cells

Advanced oral cancer has a poor prognosis because of the lack of an effective treatment. We explored the efficiency of combined treatment with triptolide and ionizing radiation for treating oral cancer. Human tongue cancer cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation. Cell proliferation, cell cycle arrest, and apoptotic influences were analyzed by FACS and immunohistochemistry. Tumor potency was examined in an in vivo human tongue cancer cells xenograft mouse model. Our results demonstrated that triptolide caused a marked reduction in colony number that was further enhanced with increasing doses of ionizing radiation. Triptolide increased apoptosis and decreased the expression of anti-apoptotic proteins. In vivo, combination treatment synergistically reduced tumor weight and volume possibly via the induction of apoptosis and reduction in anti-apoptotic protein expression. In conclusion, triptolide plus ionizing radiation treatment had synergistic anti-tumor effects, especially in vivo, and may be a promising combined modality therapy for advanced oral cancer.

Topics: Animals; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Chemotherapy, Adjuvant; Diterpenes; Epoxy Compounds; Humans; Mice; Phenanthrenes; Phytotherapy; Plant Extracts; Tongue; Tongue Neoplasms; Tripterygium; Xenograft Model Antitumor Assays

The incidence of high-risk human papillomavirus (HR-HPV) head and neck squamous cell carcinoma (HNSCC) continues to increase, particularly oropharyngeal squamous cell carcinoma (OPSCC) cases. The inactivation of the p53 tumor suppressor gene promotes a chain of molecular events, including cell cycle progression and apoptosis resistance. Reactivation of wild-type p53 function is an intriguing therapeutic strategy. The aim of this study was to investigate whether a novel compound derived from diterpene triepoxide (Minnelide™) can reactivate wild-type p53 function in HPV-positive HNSCC.. For all of our in vitro experiments, we used 2 HPV-positive HNSCC cell lines, University of Michigan squamous cell carcinoma (UM-SCC) 47 and 93-VU-147, and 2 HPV-positive human cervical cancer cell lines, SiHa and CaSki. Cells were treated with different concentrations of triptolide and analyzed for p53 activation. Mice bearing UM-SCC 47 subcutaneous xenografts and HPV-positive patient-derived tumor xenografts were treated with Minnelide and evaluated for tumor growth and p53 activation.. In HPV-positive HNSCC, Minnelide reactivated p53 by suppressing E6 oncoprotein. Activation of apoptosis followed, both in vitro and in vivo. In 2 preclinical HNSCC animal models (a subcutaneous xenograft model and a patient-derived tumor xenograft model), Minnelide reactivated p53 function and significantly decreased tumor progression and tumor volume.. Triptolide and Minnelide caused cell death in vitro and in vivo in HPV-positive HNSCC by reactivating wild-type p53 and thus inducing apoptosis. In addition, in 2 HPV-positive HNSCC animal models, Minnelide decreased tumor progression and induced apoptosis.

Topics: Animals; Antineoplastic Agents, Alkylating; Apoptosis; Carcinoma, Squamous Cell; Diterpenes; Epoxy Compounds; Head and Neck Neoplasms; Human papillomavirus 16; Humans; Mice; Organophosphates; Papillomavirus Infections; Phenanthrenes; Treatment Outcome; Tumor Suppressor Protein p53

A new phenanthrenequinone, 5-hydroxy-2,3-dimethoxy-1,4-phenanthrenequinone (1), was isolated along with a known 9,10-dihydrophenanthrenequinone, ephemeranthoquinone B (2) from an MeOH extract of Odontioda Marie Noel 'Velano' through bioassay-guided fractionation. Their structures were elucidated by spectroscopic analysis, and the compounds were tested for in vitro cytotoxic activity. The compounds showed slightly higher cytotoxicity in human oral squamous cell carcinoma and leukemic cell lines as compared with human oral normal cells. The results suggest that apoptosis may not be involved in the cytotoxicity induction.

Topics: Antineoplastic Agents, Phytogenic; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Leukemia; Orchidaceae; Phenanthrenes; Plant Extracts

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

To investigate the effect of triptolide on the proliferation and apoptosis of human epidermal squamous cell carcinoma cell line A431 in vitro.. Human epidermal squamous cell carcinoma cell line A431 was cultured. After the treatment with triptolide, the inhibition of cellular growth was determined by measuring MTT dye absorption of the living cells. Light microscope showed morphological changes. The cell cycle and apoptosis rate were assessed by flow cytometry.. Triptolide could significantly inhibit the proliferation of A431 cells in a dose- and time-dependent manner. Triptolide could also cause cell morphological changes (the number of floating cells and nuclear pyknosis increase), induce cell apoptosis, and change the distribution of cell cycle phase in A431 cells. Compared with the control group, the G( 0) /G( 1) phase A431 cell rate increased and the rate of S phase cell decreased in TP-treated group. Cell cycles were obviously inhibited by triptolide in G( 0) /G( 1) phase ( both P<0.05).. TP could play an anti-tumor role by effectively inducing cell apoptosis and inhibiting the proliferation of A431 cells.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Diterpenes; Epoxy Compounds; Humans; Phenanthrenes; Skin Neoplasms

Selectin ligands are crucial components in the interaction between endothelial cells and extravasating cancer cells and, thus, play an important role in metastasis formation. Head-and-neck squamous cell carcinoma (HNSCC) variants expressing high levels of E48, a human Ly-6 protein (E48(hi)), expressed higher levels of the fucose-generating FX enzyme and of the fucosylated E-selectin ligand sLe(a) than cells expressing low levels of E48 (E48(lo)). Signaling through E48 upregulated expression levels of these molecules in HNSCC. In this work, we provide further evidence supporting the E48-FX-sLe(a) link by showing that FX antisense oligonucleotides reduced sLe(a) expression levels in HNSCC. We also show that E48 may be causally involved in regulating expression levels in HNSCC of 2 additional enzymes involved in the biosynthesis of sLe(a), namely, ST-30 and FucTIII. Also, selectin-mediated adhesion of E48(hi) variants to activated HUVECs was significantly higher than that of E48(lo) variants. Transfection experiments utilizing sense or antisense E48 cDNA indicated that E48 may be causally involved in this adhesion. Chemokines are involved in the extravasation process of tumor cells. The release of chemoattractants from HNSCC variants differing in E48 expression was therefore analyzed. HNSCC did not release any chemoattractants but induced the release of such factors from HUVECs. Supernatants from E48(hi) variants were significantly more efficient than E48(lo) cells at inducing the release of chemoattractants from HUVECs. Transfection experiments indicated that E48 may be causally involved in the induction of chemoattractant release from HUVECs. Angiogenesis is an important manifestation of cancer-endothelium interactions. We therefore assayed for the presence of angiogenic factors in culture supernatants of HNSCC. Supernatants from E48(lo) variants contained significantly higher amounts of PDGF than E48(hi) cells. Transfection experiments indicated that E48 may be causally involved. Taken together, our results suggest that E48 controls important interaction parameters between HNSCC and endothelial cells.

Topics: Antigens, Ly; Becaplermin; Carcinoma, Squamous Cell; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Cytokines; DNA Primers; Endothelium, Vascular; Flow Cytometry; Fucosyltransferases; Gelatinases; Glycoproteins; GPI-Linked Proteins; Head and Neck Neoplasms; Humans; Mutagenesis, Site-Directed; Oligonucleotides, Antisense; Phenanthrenes; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Selectins

The carcinogenic potential of 4 highly purified polycyclic aromatic compounds (PAC) was studied in the respiratory tract of rats. Using a beeswax/trioctanoin mixture as vehicle, 10, 3 and 1 mg phenanthrene (PHE), 3 and 1 mg chrysene (CHR), 0.1 mg dibenz(a,h)anthracene (DBahA) and 6, 3 and 1 mg benzo(b)naphto(2,1-d)thiophene (BNT) were injected into the lungs of 35 female Osborne-Mendel rats per group. Benzo(a)pyrene (BaP, 0.3, 0.1 and 0.03 mg) was used as the reference substance. Whereas only one squamous cell carcinoma developed at the highest PHE dose, a dose-dependent tumor incidence was found for CHR. BNT showed a carcinogenic effect similar to CHR, but an increasing incidence of neoplasms was not seen between the median and high dose. DBahA induced carcinomas in even more than half of the animals at the dose level of 0.1 mg and, therefore, has to be classified as the most potent PAC under investigation. BaP resulted in a clear dose-response relationship. According to probit analysis of the results, the carcinogenic potencies of the PAC relative to BaP (1.00) rank as follows: DBahA, 1.91; CHR, 0.03; BNT, 0.02; and PHE, 0.001. The estimated ED10- values were 0.031 mg for BaP, 0.016 mg for DBahA, 1.02 mg for CHR, 1.65 mg for BNT and 22.84 mg for PHE.

Topics: Animals; Benz(a)Anthracenes; Carcinoma, Squamous Cell; Chrysenes; Dose-Response Relationship, Drug; Female; Injections; Lung Neoplasms; Phenanthrenes; Polycyclic Compounds; Rats; Thiophenes

As a class, octahydrophenanthrene lactones, podolactones , and related podocarpic acid derivatives have been reported to possess a wide variety of biological activities, including antileukemic activity, inhibition of plant cell growth, and hormonal and anti-inflammatory properties. In the present study, a series of synthetic intermediates derived from podocarpic acid have been prepared and evaluated with respect to their ability to inhibit human epidermoid carcinoma of the nasopharynx in vitro. The significant cytotoxicity demonstrated by methyl 6 alpha-bromo-7-oxo-O- methylpodocarpate (50% inhibition of cells at 8.85 X 10(-9) M) was markedly higher than that of the other derivatives examined. Further evaluation against L1210 and P388 lymphoid leukemias in mice failed to demonstrate significant antitumor activity.

Topics: Abietanes; Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; Humans; Leukemia L1210; Mice; Nasopharyngeal Neoplasms; Neoplasms, Experimental; Phenanthrenes

Topics: Amines; Antineoplastic Agents; Aza Compounds; Carcinoma, Squamous Cell; Culture Media; Humans; In Vitro Techniques; Naphthalenes; Nasopharyngeal Neoplasms; Phenanthrenes; Phenanthridines; Quinolines; Quinoxalines; Schiff Bases

Topics: Antineoplastic Agents; Carcinoma, Bronchogenic; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Phenanthrenes

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Cyclopentanes; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sarcoma, Experimental