Category Archives: anti-tubulin

A549, Akt, angiogenesis, Anti-angiogenic, Anti-cancer, anti-inflammatory, Anti-metastatic, anti-tubulin, apoptosis, bFGF, Breast cancer, c-Jun, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, Chemotherapy, Colon Cancer or Colorectal cancer, COX-2, Cytostatic, cytotoxic, Dendrobrium loddigesii, ERK1, G1, G2/M, HCT-116, HIF, induces apoptosis, inflammation, iNOS, JNK, Lung cancer, MDA-MB-231, metastasis, Rectal cancer, ROS, Twist, VEGF, VEGF

Moscatilin

Cancers:
Colon, lung, placenta, stomach, breast metastasis

Action: Anti-angiogenic, anti-metastatic, anti-tubulin, cytostatic, cytotoxic, cell-cycle arrest, anti-inflammatory

Stomach Cancer, Lung Cancer, Placental

The efficacy of using moscatilin, a natural anti-platelet agent extracted from the stems of Dendrobrium loddigesii, as an anti-cancer agent was studied. Results demonstrated that moscatilin exerts potent cytotoxic effect against cancer cell lines derived from different tissue origins, including those from the placenta, stomach, and lung, but not those from the liver. In addition, the mechanism of action of moscatilin may be related to its ability to induce a G2 phase arrest in responsive cells.

However, unlike some G2 arresting agents, moscatilin has no detectable inhibitory effect on cyclin B–cdc-2 kinase activity. Thus, the precise nature of its cytotoxic mechanism remains to be determined.

Results suggest that moscatilin is potentially efficacious for chemo-prevention and/or chemotherapy against some types of cancer (Ho & Chen, 2003).

Colorectal Cancer

The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on colorectal HCT-116 cells, c-Jun NH(2)-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Moscatilin induced a time-dependent arrest of the cell-cycle at G2/M, with an increase of cells at sub-G1. Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. A parallel experiment showed that SP600125 significantly inhibits Taxol and vincristine induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents.

Collectively, results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage leading to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway (Chen et al., 2008).

Anti-inflammatory

Results showed that moscatilin (10-100 microM) had a significant inhibition in a concentration-dependent manner on pro-inflammatory enzymes (COX-2 and iNOS) expression and macrophage activation under LPS (100 ng/mL) treatment.

Hypoxia-inducible factor 1 (HIF-1) alpha was reported to initiate inflammation under cytokine stimulation or hypoxic conditions. Moscatilin had significant inhibition on HIF-1 expression via down-regulation of HIF-1 mRNA without affecting cell viability, translation machinery, or proteasome-mediated degradation of HIF-1. Collective data demonstrarted that moscatilin inhibited both COX-2 and iNOS expressions after LPS treatment in RAW264.7. Furthermore, moscatilin's inhibitory effect appears to be dependent on the repression of HIF-1alpha accumulation and NF-kappaB activation (Liu et al., 2010).

Lung Cancer; Angiogenesis

Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs.

Results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy (Tsai et al., 2010).

Lung Cancer

Investigation demonstrated that non-toxic concentrations of moscatilin were able to inhibit human non-small-cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical was identified as a dominant species in the suppression of filopodia formation.

Results indicate a novel molecular basis of moscalitin inhibiting lung cancer cell motility and invasion. Moscalitin may have promising anti-metastatic potential as an agent for lung cancer therapy (Kowitdamrong, Chanvorachote, Sritularak & Pongrakhananon, 2013).

Breast Cancer; Metastasis

Moscatilin, derived from the orchid Dendrobrium loddigesii, has shown anti-cancer activity. The mechanism by which moscatilin suppresses the migration and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo was evaluated.

Moscatilin was found to significantly inhibit breast cancer MDA-MB-231 cell migration by using scratch assays and Boyden chambers.

In an MDA-MB-231 metastatic animal model, moscatilin (100 mg/kg) significantly suppressed breast cancer metastasis to the lungs and reduced the number of metastatic lung nodules and lung weight without causing any toxicity.

Results indicated that moscatilin inhibited MDA-MB-231 cell migration via Akt- and Twist-dependent pathways, consistent with moscatilin's anti-metastatic activity in vivo. Therefore, moscatilin may be an effective compound for the prevention of human breast cancer metastasis (Pai et al., 2013).

References

Chen TH, Pan SL, Guh JH, et al. (2008). Moscatilin induces apoptosis in human colorectal cancer cells: a crucial role of c-Jun NH2-terminal protein kinase activation caused by tubulin depolymerization and DNA damage. Clinical Cancer Research, 14(13), 4250-4258. doi: 10.1158/1078-0432.CCR-07-4578.


Ho CK, Chen CC. (2003). Moscatilin from the orchid Dendrobrium loddigesii is a potential anti-cancer agent. Cancer Investigation, 21(5), 729-736.


Kowitdamrong A, Chanvorachote P, Sritularak B, Pongrakhananon V. (2013). Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. BioMed Research International., 2013, 765894. doi: 10.1155/2013/765894.


Liu YN, Pan SL, Peng CY, et al. (2010). Moscatilin repressed lipopolysaccharide-induced HIF-1alpha accumulation and NF-kappaB activation in murine RAW264.7 cells. Shock, 33(1), 70-5. doi: 10.1097/SHK.0b013e3181a7ff4a.


Pai HC, Chang LH, Peng CY, et al. (2013). Moscatilin inhibits migration and metastasis of human breast cancer MDA-MB-231 cells through inhibition of Akt and Twist signaling pathway.

Journal of Molecular Medicine (Berlin), 91(3), 347-56. doi: 10.1007/s00109-012-0945-5.

Tsai AC, Pan SL, Liao CH, et al. (2010). Moscatilin, a bibenzyl derivative from the India orchid Dendrobrium loddigesii, suppresses tumor angiogenesis and growth in vitro and in vivo. Cancer Letters, 292(2), 163-70. doi: 10.1016/j.canlet.2009.11.020.

A2780, A549, Akt, angiogenesis, Anti-cancer, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tubulin, anti-tumor, Apo2L, Apo2L/TRAIL, apoptosis, Apoptotic, Breast cancer, BxPC-3, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemo-sensitizer, Colon Cancer or Colorectal cancer, Down-regulates, down-regulates MMP-9, DR5, DU145, ER, G2/M, induces apoptosis, inhibits angiogenesis, inhibits proliferation, Lung cancer, MDA-MB-231, MDA-MB-453, metastasis, Ovarian cancer, Pancreatic cancer, Pro-apoptotic, Prostate cancer, Rectal cancer, SW480, DLD-1, LS174T, TAGLN, TRAIL, various fruits, vegetables

Apigenin

Cancer:
Breast, gastrointestinal., prostate, ovarian, pancreatic

Action: Anti-proliferative effect, induces apoptosis, chemo-sensitizer

Apigenin (4′,5,7-trihydroxyflavone, 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a flavonoid found in many fruits, vegetables, and herbs, the most abundant sources being the leafy herb parsley and dried flowers of chamomile. Present in dietary sources as a glycoside, it is cleaved in the gastrointestinal lumen to be absorbed and distributed as apigenin itself. For this reason, the epithelium of the gastrointestinal tract is exposed to higher concentrations of apigenin than tissues at other locations. This would also be true for epithelial cancers of the gastrointestinal tract. There is evidence that the actions of apigenin might hinder the ability of gastrointestinal cancers to progress and spread.

Induces Apoptosis, Anti-metastatic

Apigenin has been shown to inhibit cell growth, sensitize cancer cells to elimination by apoptosis, and hinder the development of blood vessels to serve the growing tumor. It also has actions that alter the relationship of the cancer cells with their microenvironment. Apigenin is able to reduce cancer cell glucose uptake, inhibit remodeling of the extracellular matrix, inhibit cell adhesion molecules that participate in cancer progression, and oppose chemokine signaling pathways that direct the course of metastasis into other locations. As such, apigenin may provide some additional benefit beyond existing drugs in slowing the emergence of metastatic disease (Lefort, 2013).

Chemo-sensitizer, Induces Apoptosis

Choi & Kim (2009) investigated the effects of combined treatment with 5-fluorouracil and apigenin on proliferation and apoptosis, as well as the underlying mechanism, in human breast cancer MDA-MB-453 cells. The MDA-MB-453 cells, which have been shown to overexpress ErbB2, were resistant to 5-fluorouracil; 5-fluorouracil exhibited a small dose-dependent anti-proliferative effect, with an IC50 of 90 microM. Interestingly, combined treatment with apigenin significantly decreased the resistance. Cellular proliferation was significantly inhibited in cells exposed to 5-fluorouracil at its IC50 and apigenin (5, 10, 50 and 100 microM), compared with proliferation in cells exposed to 5-fluorouracil alone.

This inhibition in turn led to apoptosis, as evidenced by an increased number of apoptotic cells and the activation of caspase-3. Moreover, compared with 5-fluorouracil alone, 5-fluorouracil in combination with apigenin at concentrations >10 microM exerted a pro-apoptotic effect via the inhibition of Akt expression.

Taken together, results suggest that 5-fluorouracil acts synergistically with apigenin inhibiting cell growth and inducing apoptosis via the down-regulation of ErbB2 expression and Akt signaling (Choi, 2009).

Breast Cancer, Prostate Cancer

Two flavonoids, genistein and apigenin, have been implicated as chemo-preventive agents against prostate and breast cancers; however, the mechanisms behind their respective cancer-protective effects may vary significantly. It was thought that the anti-proliferative action of these flavonoids on prostate (DU-145) and breast (MDA-MB-231) cancer cells expressing only estrogen receptor (ER) β is mediated by this ER subtype. It was found that both genistein and apigenin, although not 17β-estradiol, exhibited anti-proliferative effects and pro-apoptotic activities through caspase-3 activation in these two cell lines. In yeast transcription assays, both flavonoids displayed high specificity toward ERβ transactivation, particularly at lower concentrations.

However, in mammalian assay, apigenin was found to be more ERβ-selective than genistein, which has equal potency in inducing transactivation through ERα and ERβ. Small interfering RNA-mediated down-regulation of ERβ abrogated the anti-proliferative effect of apigenin in both cancer cells but did not reverse that of genistein. These results unveil that the anti-cancer action of apigenin is mediated, in part, by ERβ. The differential use of ERα and ERβ signaling for transaction between genistein and apigenin demonstrates the complexity of phytoestrogen action in the context of their anti-cancer properties (Mak, 2006).

Ovarian Cancer

Id1 (inhibitor of differentiation or DNA binding protein 1) contributes to tumorigenesis by stimulating cell proliferation, inhibiting cell differentiation and facilitating tumor neoangiogenesis. Elevated Id1 is found in ovarian cancers and its level correlates with the malignant potential of ovarian tumors. Therefore, Id1 is a potential target for ovarian cancer treatment. It has been demonstrated that apigenin inhibits proliferation and tumorigenesis of human ovarian cancer A2780 cells through Id1. Apigenin has been found to suppress the expression of Id1 through activating transcription factor 3 (ATF3). These results may elucidate a new mechanism underlying the inhibitory effects of apigenin on cancer cells (Li, 2009).

Pancreatic Cancer

Simultaneous treatment or pre-treatment (0, 6, 24 and 42 hours) of apigenin and chemotherapeutic drugs and various concentrations (0-50µM) were assessed using the MTS cell proliferation assay. Simultaneous treatment with apigenin (0,13, 25 or 50µM) and chemotherapeutic drugs 5-fluorouracil (5-FU, 50µM) or gemcitabine (Gem, 10µM) for 60 hours resulted in less-than-additive effect (p<0.05). Pre-treatment for 24 hours with 13µM of apigenin, followed by Gem for 36 hours was optimal to inhibit cell proliferation.

Pre-treatment of cells with 11-19µM of apigenin for 24 hours resulted in 59-73% growth inhibition when followed by Gem (10µM, 36h). Pre-treatment of human pancreatic cancer cells BxPC-3 with low concentrations of apigenin hence effectively aids in the anti-proliferative activity of chemotherapeutic drugs (Johnson, 2013).

Induces Apoptosis, Inhibits Angiogenesis and Metastasis.

Preclinical studies have also shown that Ocimum sanctum L. and some of the phytochemicals it contains (including apigenin) prevents chemical-induced skin, liver, oral., and lung cancers. These effects are thought to be mediated by increasing the anti-oxidant activity, altering gene expression, inducing apoptosis, and inhibiting angiogenesis and metastasis. The aqueous extract of Ocimum sanctum L. has been shown to protect mice against γ-radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. In particular, important phytochemicals like apigenin have also been shown to prevent radiation-induced DNA damage. This warrants its future research to establish its activity and utility in cancer prevention and treatment (Baliga, 2013).

Lung Cancer

Apigenin has been found to induce apoptosis and cell death in lung epithelium cancer (A549) cells with an IC50 value of 93.7 ± 3.7 µM for 48 hours treatment. Target identification investigations using A549 cells and in cell-free systems demonstrate that apigenin depolymerized microtubules and inhibited reassembly of cold depolymerized microtubules of A549 cells. Again apigenin inhibited polymerization of purified tubulin with an IC50 value of 79.8 ± 2.4 µM. Interestingly, apigenin also showed synergistic anti-cancer effects with another natural anti-tubulin agent, curcumin. Apigenin and curcumin synergistically induce cell death and apoptosis and also block cell-cycle progression at G2/M phase of A549 cells.

Understanding the mechanism of the synergistic effect of apigenin and curcumin could help to develop anti-cancer combination drugs from cheap and readily available nutraceuticals (Choudhury, 2013).

Induces Apoptosis

It has been shown that the dietary flavonoid apigenin binds and inhibits adenine nucleotide translocase-2 (ANT2), resulting in enhancement of Apo2L/TRAIL-induced apoptosis by up-regulation of DR5, making it a potential cancer therapeutic agent. Apigenin has been found to enhance Apo2L/TRAIL-induced apoptosis in cancer cells by inducing DR5 expression through binding ANT2. Similarly to apigenin, knockdown of ANT2 enhanced Apo2L/TRAIL-induced apoptosis by up-regulating DR5 expression at the post-transcriptional level.

Moreover, silencing of ANT2 attenuated the enhancement of Apo2L/TRAIL-induced apoptosis by apigenin. These results suggest that apigenin Up-regulates DR5 and enhances Apo2L/TRAIL-induced apoptosis by binding and inhibiting ANT2. ANT2 inhibitors like apigenin may hence contribute to Apo2L/TRAIL therapy (Oishi, 2013).

Colorectal Cancer

Apigenin has anti-proliferation, anti-invasion and anti-migration effects in three kinds of colorectal adenocarcinoma cell lines, namely SW480, DLD-1 and LS174T. Proteomic analysis with SW480 indicated that apigenin up-regulated the expression of transgelin (TAGLN) in mitochondria to exert its anti-tumor growth and anti-metastasis effects. Apigenin decreased the expression of MMP-9 in a dose-dependent manner. Transfection of three truncated forms of TAGLN and wild type has identified TAGLN as a repressor of MMP-9 expression.

This research provides direct evidence that apigenin inhibits tumor growth and metastasis both in vitro and in vivo. Apigenin up-regulates TAGLN and down-regulates MMP-9 expression through decreasing phosphorylation of Akt at Ser473 and in particular Thr308 to prevent cancer cell proliferation and migration (Chunhua, 2013).

References

Baliga MS, Jimmy R, Thilakchand KR, et al. (2013). Ocimum Sanctum L (Holy Basil or Tulsi) and Its Phytochemicals in the Prevention and Treatment of Cancer. Nutr Cancer, 65(1):26-35. doi: 10.1080/01635581.2013.785010.

 

 

Choi EJ, Kim GH. (2009). 5-Fluorouracil combined with apigenin enhances anti-cancer activity through induction of apoptosis in human breast cancer MDA-MB-453 cells. Oncol Rep, 22(6):1533-7.

 

Choudhury D, Ganguli A, Dastidar DG, et al. (2013). Apigenin shows synergistic anti-cancer activity with curcumin by binding at different sites of tubulin. Biochimie, 95(6):1297-309. doi: 10.1016/j.biochi.2013.02.010.

 

Chunhua L, Donglan L, Xiuqiong F, et al. (2013). Apigenin up-regulates transgelin and inhibits invasion and migration of colorectal cancer through decreased phosphorylation of AKT. J Nutr Biochem. doi: 10.1016/j.jnutbio.2013.03.006.

 

Johnson JL, Gonzalez de Mejia E. (2013). Interactions between dietary flavonoids apigenin or luteolin and chemotherapeutic drugs to potentiate anti-proliferative effect on human pancreatic cancer cells, in vitro. Food Chem Toxicol, 20:83-91. doi: 10.1016/j.fct.2013.07.036.

 


Lefort ƒC, Blay J. (2013). Apigenin and its impact on gastrointestinal cancers. Mol Nutr Food Res, 57(1):126-44. doi: 10.1002/mnfr.201200424.

 

Li ZD, Hu XW, Wang YT & Fang J. (2009). Apigenin inhibits proliferation of ovarian cancer A2780 cells through Id1. FEBS Letters, 583(12):1999-2003 doi:10.1016/j.febslet.2009.05.013.

 

Mak P, Leung YK, Tang WY, Harwood C & Ho SM. (2006). Apigenin suppresses cancer cell growth through ERβ. Neoplasia, 8(11):896–904.

 

Oishi M, Iizumi Y, Taniguchi T, et al. (2013). Apigenin Sensitizes Prostate Cancer Cells to Apo2L/TRAIL by Targeting Adenine Nucleotide Translocase-2. PLoS One, 8(2):e55922. doi: 10.1371/journal.pone.0055922.