Molecular modes of action of cantharidin in tumor cells

Efferth, Thomas; Rauh, Rolf; Kahl, Stefan; Tomičić, Maja; Böchzelt, Herbert; Tome, Margaret E.; Briehl, Margaret M.; Bauer, Rudolf; Kaina, Bernd

doi:10.1016/j.bcp.2004.12.003

Cited by 89 publications

(66 citation statements)

References 28 publications

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“…CTD, the active ingredient of blister beetle, has been reported to be an inhibitor of protein phosphatases 1 and 2a (17) that have biological activity, such as cytotoxic effects to induce DNA damage in cancer cells (18) and G 2 /M phase arrest of cell-cycle distribution and induction of apoptosis (19,20). Furthermore, CTD has also been reported to induce apoptosis in human cancer, such as bladder (21,22), breast (23), liver cancer (24) and multiple myeloma (25).…”

Section: Abstract Cantharidin (Ctd) a Component Of Natural Mylabrismentioning

confidence: 99%

Cantharidin Impairs Cell Migration and Invasion of Human Lung Cancer NCI-H460 Cells via UPA and MAPK Signaling Pathways

Hsia

Hsiao

et al. 2016

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Abstract. Cantharidin (CTD), a component of natural mylabris (Mylabris phalerata Pallas), has been shown to have biological activities and induce cell death in many human and the results indicated that CTD inhibited the enzymatic activities of MMP-2/-9 of NCI-H460 cells. Western blotting was used to examine the protein expression of NCI-H460 cells after incubation with CTD and the results showed that CTD decreased the expression of MMP-2/-9, focal adhesion kinase (FAK), Ras homolog gene family, member A (Rho A), phospho-protein kinase B (AKT) (Thr308)(p-AKT(308)), phospho-extracellular signal-regulated kinase1/2 (p-ERK1/2), phospho-p38 mitogen-activated protein (MAP) kinase (p-p38), phospho c-Jun N-terminal kinase 1/2 (p-JNK1/2), nuclear factor-ĸB (NF-ĸB) and urokinase plasminogen activator (UPA). Furthermore, confocal laser microscopy was used to confirm that CTD suppressed the expression of NF-ĸB p65, but did not significantly affect protein kinase C (PKC) translocation in NCI-H460 cells. Based on those observations, we suggest that CTD may be used as a novel anticancer metastasis agent for lung cancer in the future.Lung cancer is the most common cancer among women and men in Taiwan and it is the major cause of death in cancerrelated diseases in the developed world. Neoplastic metastasis is a major cause of cancer-mediated death in humans (1, 2). For tumor metastasis, epithelial cancer cells have to migrate from the original primary tumor mass via breaking their cellcell contacts (adherens junctions) to form cancer mass in a new site (3, 4); thus, tumor metastasis involves cell attachment (adhension), migration and invasion in order to form a new tumor in another site of the body. Inhibiting cancer cell metastasis is one of the important steps for cancer therapy and research (5). Numerous evidence have shown that multiple factors involved in tumor metastasis, such as the activation of PI3K/Akt pathway (6), matrix metalloproteinases (MMPs)-enzymes that can degrade the extracellular matrix and 5989

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Section: Abstract Cantharidin (Ctd) a Component Of Natural Mylabrismentioning

confidence: 99%

Cantharidin Impairs Cell Migration and Invasion of Human Lung Cancer NCI-H460 Cells via UPA and MAPK Signaling Pathways

Hsia

Hsiao

et al. 2016

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“…Such toxic effects will likely prevent cantharidin from being developed for mainstream oncology. Still, when applied at lower concentrations (f2 -5 AM), cantharidin can elicit a strong apoptotic response in many types of tumor cells (9 -11), characterized by membrane blebbing, caspase activation, DNA fragmentation (11), phosphorylation/activation of p53, and increased levels of both p21 waf1/cip1 (10) and Bax (9). Cantharidin treatment has also been shown to produce a decrease in the levels of two proteins that suppress apoptosis: bcl-2 and survivin (9).…”

Section: Introductionmentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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Cantharidin, a natural vesicant, inhibits the activity of several PPP family phosphatases, displays antitumor activity, and induces apoptosis in many types of tumor cells. However, the molecular mechanisms underlying the antitumor activity of cantharidin are not clear. Here, doseresponse studies confirm a strong correlation between the suppression of phosphatase activity and cell death. Flow cytometry analysis indicates that before apoptosis, cantharidin delays cell cycle progression following DNA replication with no apparent effect on G 1 -S or S-G 2 phase progression. In contrast, studies with double thymidinesynchronized populations of cells indicate that cantharidin can rapidly arrest growth when added during G 2 or early M phase. Immunostaining indicates that cell cycle arrest occurs before the completion of mitosis and is associated with the appearance of aberrant mitotic spindles. Live cell imaging with time-lapse microscopy shows that cantharidin disrupts the metaphase alignment of chromosomes and produces a prolonged mitotic arrest, with the onset of apoptosis occurring before the onset of anaphase. To explore the contribution of individual phosphatases, antisense oligonucleotides and small interfering RNA were developed to suppress the expression of cantharidinsensitive phosphatases. The suppression of PP2AA, but not PP2AB, is sufficient to induce metaphase arrest, during which time lagging chromosomes are observed moving between the spindle poles and the metaphase plate. Immunostaining revealed slightly abnormal, yet predominately bipolar, mitotic spindles. Nonetheless, after a 10-to 15-hour delay, the cells enter anaphase, suggesting that an additional cantharidin-sensitive phosphatase is involved in the progression from metaphase into anaphase or to prevent the onset of apoptosis in cells arrested during mitosis.

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“…CCCs are among numerous TCMs used for cancer treatment and have been used in clinical settings in China for various types of diseases, such as bronchial asthma, breast, liver, lung and digestive tract tumors (9). It has been demonstrated in leukemia cells that cantharides are inhibitors of protein phosphatase1 and 2A (36). Cantharidin has been demonstrated to induce apoptosis by a p53-dependent mechanism (29).…”

Section: Discussionmentioning

confidence: 99%

“…Cantharidin has been demonstrated to induce apoptosis by a p53-dependent mechanism (29). Such effects may be mediated by any of the various mechanisms in which cantharides are involved (36)(37)(38)(39)(40)(41). However, studies regarding the molecular basis of the effects of cantharides in gastric cancer cell lines have been limited.…”

Section: Discussionmentioning

confidence: 99%

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line

Sun

Zhang

Mao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the inhibitory effect of compound cantharides capsules (CCCs) on the viability and apoptosis of human gastric cancer cell lines, BGC-823 and SGC-7901, and to detect its regulation of gene expression levels, as well as its inhibition mechanisms. Each cell line was grouped into a control group, CCC serum group, 5-fluorouracil (5-FU) group, combination therapy group (CCC serum + 5-FU) and serum control group. Growth curves were measured and flow cytometry was used to detect cell apoptosis and cell viability. The mRNA expression level of proliferation-related C-MYC and p53 genes were assayed by reverse transcription-quantitative polymerase chain reaction. Protein phosphorylation levels of proliferating cell nuclear antigen, p38 mitogen-activated protein kinase, extracellular signal-related kinase 1/2, c-Jun N-terminal kinase (JNK) and IκB were assayed by western blotting. The combined CCC serum and 5-FU group exhibited a higher inhibition rate in both cell lines and CCC serum therapy demonstrated a similar effect to 5-FU treatment, as demonstrated in the MTT and cell growth assay. Combined therapy significantly decreased the C-MYC mRNA expression levels and increased p53 mRNA expression levels (P<0.05). Combined therapy of 5-FU and CCC was more significant compared with CCC serum or 5-FU only (P<0.05). P38 and JNK-related protein phosphorylation are involved in apoptosis initiated by CCC combined 5-FU therapy. Combined therapy was able to significantly inhibit human gastric cancer cell growth (P<0.05), and advance cell apoptosis compared with CCC serum only. CCC serum resulted in downregulation of the c-Myc gene and upregulation of the p53 gene. p38 and JNK-related protein phosphorylation is involved in the inhibition of cell viability and apoptosis of human gastric cancer cell lines. IntroductionIn the last 5 years, gastric cancer has become the most frequent cause of cancer-related fatality, making it the fifth most common cancer in the world, with approximately 952,000 new cases diagnosed in 2012 (1,2). In China, gastric cancer is one of the most common cancers and the incidence ranks third among all malignant tumors, after lung and liver cancer in men and after breast and lung cancer in women (3). Despite the fact that diagnostic and therapeutic approaches have advanced in the past decade, the prognosis is still unclear due to the high recurrence (4).5-fluorouracil (5-FU) is a chemotherapeutic agent that is currently the most widely used drug choice for the treatment of solid tumors, such as metastatic colorectal cancer and gastric cancer (5-8). Alternatively, Traditional Chinese Medicine (TCM) is a multi-channel, multi-layer and multi-target method for treating cancer as an alternative to surgery, radiotherapy, chemotherapy and biological therapy (9). TCM involves the use of complicated ingredients that may promote the inhibition and apoptosis of cancer cells (9). Compound cantharides capsules (CCC) are one of the most common TCMs that contain cantharidi...

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Molecular modes of action of cantharidin in tumor cells

Cited by 89 publications

References 28 publications

Cantharidin Impairs Cell Migration and Invasion of Human Lung Cancer NCI-H460 Cells via UPA and MAPK Signaling Pathways

Cantharidin Impairs Cell Migration and Invasion of Human Lung Cancer NCI-H460 Cells via UPA and MAPK Signaling Pathways

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line

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