Category Archives: various fruits

Anti-cancer, anti-inflammatory, AT6.3, Breast cancer, Breast cancer cell lines, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemotherapy, IKK, inflammation, inhibits NF-κB, MDR, Multi-Drug Resistance, P-gp, PTK, various fruits, vegetables

Biochanin A

Cancer: Breast

Action: Multi-drug resistance, anti-inflammatory, chemo-preventive

Biochanin is a derivative found in fruits, vegetables, plant-derived beverages, and herbal dietary supplements. It is isolated from a range of plants, including red clover, soy, alfalfa sprouts, and garbanzo beans (Trifolium pratense (L.), Glycine max [(L.) Merr.], Medicago sativa (L.), Cicer arietinum (L.))

MDR; Breast Cancer

Multi-drug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant-derived beverages and herbal dietary supplements not only have anti-cancer properties, but may also modulate P-gp activity. To further elucidate this, the effect of biochanin on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant) was therefore examined.

The IC50 value of DNM in the resistant cells was about 22 times higher than that in the sensitive cells, indicating an over-expression of P-gp in the resistant cells, MCF-7/ADR. Biochanin was found to significantly decrease the IC50 value of DNM. Biochanin also showed a significant increase in [3H]-DNM accumulation, increasing by 454.3±19.5% in the resistant cells. Moreover, biochanin significantly decreased DNM efflux from MCF-7/ADR cells compared with the control. These results suggest that biochanin may reverse MDR by inhibiting the P-gp function (Chung et al., 2005).

Chemo-preventive

Biochanin A (BCA), a major isoflavone in red clover and many other legumes, has been reported to display estrogenic as well as cancer chemo-preventive properties. Ingested BCA is known to display low bioavailability due to poor solubility, extensive metabolism and rapid clearance. Esters of bioactive isoflavones are known to increase metabolic stability and bioavailability following local rather than systemic administration (Fokialakis et al., 2012).

Anti-inflammatory

Biochanin inhibits NF-κB activation not only by blocking the upstream IKK, but also PTK that phosphorylate tyrosine residues of IκBα. The double-edged sword effect of inhibition of NF-κB via inhibition of both serine/threonine kinase and PTK by biochanin might show useful therapeutic value against activities of cells that lead to tumorigenesis and inflammation (Manna et al., 2012).

References

Chung SY, Sung MK, Kim NH, et al. (2005). Inhibition of P-glycoprotein by natural products in human breast cancer cells. Archives of Pharmacal Research, 28(7):823-828. doi: 10.1007/BF02977349


Fokialakis N, Alexi X, Aligiannis N, et al. (2012). Ester and carbamate ester derivatives of Biochanin A: synthesis and in vitro evaluation of estrogenic and anti-proliferative activities. Bioorg Med Chem, 20(9):2962-70. doi: 10.1016/j.bmc.2012.03.012.


Manna SK. (2012). Double-edged sword effect of biochanin to inhibit nuclear factor kappaB: suppression of serine/threonine and tyrosine kinases. Biochem Pharmacol, 83(10):1383-92. doi: 10.1016/j.bcp.2012.02.011.

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.