Cinnamaldehyde and cinnamaldehyde-derived compounds are candidates for the development of anticancer drugs that have received extensive research attention. In this review, we summarize recent findings detailing the positive and negative aspects of cinnamaldehyde and its derivatives as potential anticancer drug candidates. Furthermore, we describe the in vivo pharmacokinetics and metabolism of cinnamaldehydes. The oxidative and antioxidative properties of cinnamaldehydes, which contribute to their potential in chemotherapy, have also been discussed. Moreover, the mechanism(s) by which cinnamaldehydes induce apoptosis in cancer cells have been explored. In addition, evidence of the regulatory effects of cinnamaldehydes on cancer cell invasion and metastasis has been described. Finally, the application of cinnamaldehydes in treating various types of cancer, including breast, prostate, and colon cancers, has been discussed in detail. The effects of cinnamaldehydes on leukemia, hepatocellular carcinoma, and oral cancer have been summarized briefly. Copyright © 2016 John Wiley & Sons, Ltd.

Background:DJ-1 (PARK7) was reported as an oncogene in a Ras-dependent manner. Recent studies have shown that DJ-1 stimulates cell proliferation, cell invasion, and cancer metastasis. However, the molecular mehchanism by which DJ-1 induces cancer cell invasion and metastasis remains unclear.Methods:Breast cancer cells were transfected with DJ-1 siRNA or DJ-1 overexpression to investigate the effect of DJ-1 on KLF17 expression. ID-1 luciferase promoter assay was performed to evaluate DJ-1-dependent KLF17 expression changes. In addition, Epistasis analysis of DJ-1 and KLF17 was performed to evaluate their regulatory interactions. Ras inhibitors were pretreated to determine whether DJ-1 regulates cell invasion in a Ras-dependent manner.Results:In the present study, we found increased DJ-1 expression in highly invasive breast cancer cells as compared with non-metastatic cells. Furthermore, DJ-1 promoted breast cancer cell invasion by downregulating E-cadherin and increasing Snail expression. Interestingly, exogenous DJ-1 overexpression markedly decreased mRNA and protein expression of KLF17, the EMT negative regulator. These data were confirmed by ID-1 promoter activity, which is directly regulated by DJ-1-dependent KLF17 transcription factor. Epistasis analysis showed that KLF17 overexpression overcomes increased cell invasion by DJ-1, suggesting that KLF17 might be one of the downstream signalling molecules of DJ-1. Acceleration of cell invasion by DJ-1 was alleviated by Ras inhibitors, suggesting that DJ-1 cooperates with Ras to increase cell invasion.Conclusion:Altogether, these data suggest for the first time that DJ-1 acts as an EMT-positive regulator in breast cancer cells via regulation of the KLF17/ID-1 pathway.

No abstract

Since epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and in maintaining cancer stem cell properties, EMT is emerging as a therapeutic target for inhibiting the metastatic progression of cancer cells. 2'-Hydroxycinnamaldehyde (HCA) and its derivative, 2'-benzoyloxycinnamaldehyde, have recently been suggested as promising therapeutic candidates for cancer treatment. The purpose of this study is to investigate the anti-metastatic effect of HCA on breast cancer and the molecular mechanisms by which HCA regulates the transcriptional program during EMT. HCA induces epithelial reversion at nanomolar concentrations by suppressing Snail via the nuclear translocalization of GSK-3β, which results in the transcriptional upregulation of E-cadherin. HCA also activates the transcription factor KLF17, which suppresses Id-1, indicating that HCA inhibits EMT by multiple transcriptional programs. Further, HCA treatment significantly inhibits lung metastasis in a mouse orthotopic breast cancer model. This study demonstrates the anti-metastatic effect of the non-toxic natural compound HCA through attenuation of EMT in a breast cancer model.

2'-Benzoyloxycinnamaldehyde (BCA) is a promising antitumor agent which induces cancer cells apoptosis via reactive oxygen species (ROS) generation. BCA shows more effective antiproliferation in MDA-MB-435 than in MCF-7 breast cancer cells. DJ-1 has been known to protect cells against oxidative stress as an antioxidant because of its cysteine residues sensitive to oxidative stress. In the present study, we evaluated the mechanism of DJ-1 for cell protection from oxidative stress after BCA treatment in MCF-7 cell. BCA upregulates the expression of DJ-1 in MCF-7 cells. However, DJ-1 expression decreased continuously for 24 h after BCA treatment in MDA-MB-435 cells. DJ-1 knockdown sensitized MCF-7 cells to BCA, on the contrary, DJ-1 overexpression induced MDA-MB-435 cells less sensitive to BCA. Confocal microscopic observation showed that only in MCF-7 cells BCA increased the overlapped signal between mitochondria and DJ-1 protein. Mitochondrial membrane potential (MMP) was decreased in MDA-MB-435 cells by BCA, and DJ-1 overexpression inhibited BCA-induced MMP decrease in these cells. On the contrary, DJ-1 knockdown in MCF-7 induced MMP perturbation by BCA. These findings suggest that DJ-1 upregulation protects MCF-7 cells from BCA via inhibiting mitochondrial damage.

A series of compounds 5-amino-2-ethylmercapto-4-phenyl-6-subistitutedthieno[2,3-d]pyrimidines (8a-d), 4-chloro-7-ethylmercapto-9-phenylpyrimido[5 0 ,4 0 :4,5]thieno[3,2-d]triazine (9), and 2-ethylmercapto-8-oxo-4-phenyl-7-(4-chlorophenyl)pyrimido [4 0 ,5 0 :4,5]thieno[2,3-d]pyrimidine (10) were synthesized and their structures were confirmed by 1 H NMR, 13 C NMR, and MS. All compounds were evaluated for their IC 50 values against three cancer cell lines (MCF-7, HUH-7 and BHK) and WISH cells. The IC 50 of compound (8d) was calculated for each cell line. Interestingly, the IC 50 for the normal human amnion WISH cell line was much higher (723 μg/mL) than those found for the tumor cell lines BHK (17 μg/mL), HUH-7 (5.8 μg/mL), and MCF-7 (8.3 μg/mL). The proliferation inhibition of normal (WISH) and tumor (BHK, HUH-7, and MCF-7) cells by compound (8d) was investigated using MTT assay, and the IC 50 was calculated after 48 h of treatment for each cell line.

No abstract

Breast cancer is the most common neoplastic disorder diagnosed in women.The main goal of this study was to explore the effect of melatonin against breast cancer metastasis and compared this with the actions of taxol (a well-known chemotherapeutic drug), and the impact of their combination against breast cancer metastasis. Melatonin showed no cytotoxic effect while taxol showed antiproliferative and cytotoxic effects on MCF-7 and MDA-MB-231 cells.Furthermore, melatonin inhibited the generation of reactive oxygen species. Melatonin and taxol clearly decreased cell migration and invasion at low doses, especially those matching the normal physiological concentration at night.Melatonin and taxol markedly reduced DJ-1 and ID-1 and increased KLF17 messenger RNA and protein expression levels. The present results also showed that melatonin and taxol induced GSK3-β nuclear and Snail cytosolic localization. These changes were accompanied by a concurrent rise in E-cadherin expression. The above data show that normal levels of melatonin may help in preventing breast cancer metastasis through inhibiting DJ-1/ KLF17/ID-1 signaling pathway. The combination of melatonin and taxol is a potent candidate against breast cancer metastasis, better than using melatonin or taxol as a single drug. K E Y W O R D S breast cancer invasion, DJ-1, KLF17, melatonin, taxol J Cell Biochem. 2019;120:3945-3957.wileyonlinelibrary.com/journal/jcb