2--benzoyloxycinnamaldehyde and cinnamaldehyde

Cancer is known as a leading cause of death worldwide. In the last two decades, the incidence of cancer has been dramatically increased mostly due to lifestyle changes. The importance of this issue has attracted further attention to discover novel therapies to prevent and treat cancers. According to previous studies, drugs used to treat cancer have shown significant limitations. Therefore, the role of herbal medicines alone or in combination with chemotherapy drugs has been extensively studied in cancer treatment. Cinnamon is a natural component showing a wide range of pharmacological functions including anti-oxidant, anti-microbial and anti-cancer activities. Impaired apoptosis plays critical roles in the initiation and progression of cancer. Increasing evidence indicates that cinnamon, as a therapeutic agent, has anti-cancer effects via affecting numerous apoptosis-related pathways in cancer cells. Here, we highlighted anticancer properties of cinnamon, particularly through targeting apoptosis-related mechanisms.

Topics: Acrolein; Animals; Antineoplastic Agents; Apoptosis; Benzoates; Cell Line, Tumor; Cinnamomum zeylanicum; Eugenol; Humans; Plant Extracts

Multifunctional trans-cinnamaldehyde (CA) and its analogs display anti-cancer properties, with 2-benzoyloxycinnamaldehyde (BCA) and 5-fluoro-2-hydroxycinnamaldehyde (FHCA) being identified as the ortho-substituted analogs that possess potent anti-tumor activities. In this study, BCA, FHCA and a novel analog 5-fluoro-2-benzoyloxycinnamaldehyde (FBCA), were demonstrated to decrease growth and colony formation of human colon-derived HCT 116 and mammary-derived MCF-7 carcinoma cells under non-adhesive conditions. The 2-benzoyloxy and 5-fluoro substituents rendered FBCA more potent than BCA and equipotent to FHCA. The cellular events by which these cinnamaldehydes caused G(2)/M phase arrest and halted proliferation of HCT 116 cells were thereby investigated. Lack of significant accumulation of mitosis marker phospho-histone H3 in cinnamaldehyde-treated cells indicated that the analogs arrested cells in G(2) phase. G(2) arrest was brought about partly by cinnamaldehyde-mediated depletion of cell cycle proteins involved in regulating G(2) to M transition and spindle assembly, namely cdk1, cdc25C, mad2, cdc20 and survivin. Cyclin B1 levels were found to be increased, which in the absence of active cdk1, would fail to drive cells into M phase. Concentrations of cinnamaldehydes that brought about dysregulation of levels of cell cycle proteins also caused tubulin aggregation, as evident from immunodetection of dose-dependent tubulin accumulation in the insoluble cell lysate fractions. In a cell-free system, reduced biotin-conjugated iodoacetamide (BIAM) labeling of tubulin protein pretreated with cinnamaldehydes was indicative of drug interaction with the sulfhydryl groups in tubulin. In conclusion, cinnamaldehydes treatment at proapoptotic concentrations caused tubulin aggregation and dysegulation of cell cycle regulatory proteins cdk1 and cdc25C that contributed at least in part to arresting cells at G(2) phase, resulting in apoptotic cell death characterized by emergence of cleaved forms of caspase 3 and poly (ADP-ribose) polymerase (PARP). Results presented in this study have thus provided further insights into the intricate network of cellular events by which cinnamaldehydes induce tumor cell death.

Topics: Acrolein; Antineoplastic Agents; Apoptosis; Benzoates; Caspase 3; Cell Cycle Proteins; Cell Line, Tumor; Fungal Proteins; G2 Phase Cell Cycle Checkpoints; Gene Expression; Histones; Humans; Poly(ADP-ribose) Polymerases; Tubulin; Virulence Factors

The natural product 2'-hydroxycinnamaldehyde (HCA) and its analogue, 2'-benzoyloxycinnamaldehyde (BCA), have been previously shown to have antiproliferative and proapoptotic effects in vitro and inhibit tumor growth in vivo. In this study, we use structure-activity analysis to define structural features that are important for the activity of cinnamaldehyde analogues. Our results emphasize an important role for both the propenal group as well as the modification at the 2'-position. Further studies were aimed to characterize the mechanism of action of BCA. Exposure to BCA induced cell death via caspase-dependent and -independent pathways. Cell death was not due to autophagy or necrosis as a result of energy depletion or induction of reactive oxygen species. Our findings have important implications for future drug design and highlight the importance of defining molecular drug targets for this promising class of potential anticancer agents.

Topics: Acrolein; Antineoplastic Agents, Phytogenic; Apoptosis; Autophagy; Benzoates; Cell Line, Tumor; Cinnamates; Drug Design; Humans; Proteasome Endopeptidase Complex; Structure-Activity Relationship

Cinnamaldehyde from the bark of Cinnamomum cassia has been reported to have antitumor activity mediated by the inhibition of farnesyl transferase. We assessed in vivo the chemo-preventive effect of cinnamaldehydes on H-ras12V-induced hepatocellular carcinoma formation. A mouse model of hepatocellular carcinoma was established by using the transgene of mutated H-ras12V under the regulation of albumin enhancer/promoter. When treated with cinnamaldehyde for 10 weeks, hepatic tumor development was delayed with 2'-benzoyloxycinnamaldehyde (BCA) compared with control hepatocellular carcinoma formation. The effect of 2'-hydroxycinnamaldehyde (HCA) was comparable. The number of lesions and the size of each lesion were significantly reduced by BCA. Cell proliferation in the lesion was detected by incorporation of 5-bromo-2'-deoxyuridine (BrdU). BCA increased the number of splenocytes, concanavalin A-stimulated splenocyte proliferation and the infiltration of lymphocytes into liver. Data suggest that the delayed hepatic tumor development observed with BCA could be mediated by a long-term immunostimulating effect on T cells.

Topics: Acrolein; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Benzoates; Carcinoma, Hepatocellular; Cell Proliferation; Female; Genes, ras; Hepatocytes; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NIH 3T3 Cells; Spleen; Tumor Burden

The protein binding characteristic of 2'-Benzoyloxycinnamaldehyde (BCA) was investigated, which has demonstrated a potent antitumor effect against several human solid tumor cell lines and in human tumor xenograft nude mice. Protein binding of BCA in human serum was 86 +/- 0.91% and the predominant binding protein of BCA was fatty-acid-free human serum albumin (HSA) (81 +/- 0.91%). The binding of BCA to HSA was outlined by one class, and Ka and n of BCA were 1.65 x 10(5) M(- 1) and 0.374, respectively. Displacement studies with fluorescence probes suggested that BCA mainly binds to site I on HSA, and BCA-induced enhancement in site II binding. The limited drug-drug interaction experiments suggested that BCA influences both site I and site II drug-HSA bindings via different mechanisms; a competitive displacement and a probable allosteric conformational change in HSA, respectively.

Topics: Acrolein; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Antineoplastic Agents; Benzoates; Diazepam; Dose-Response Relationship, Drug; GABA Modulators; Humans; Immunoglobulin G; Kinetics; Orosomucoid; Phenylbutazone; Protein Binding; Serum Albumin; Temperature; Warfarin