MCF-7/ADR | Botanical Oncology

Cancer: Colon, breast, acute myeloid leukemia

Action: MDR, aromatase inhibition, induces apoptosis

Induces Apoptosis, Colorectal Cancer

Puerarin is isolated from Pueraria radix (Pueraria lobata [(Willd.) Ohwi]) and has beneficial effects on cardiovascular, neurological, and hyperglycemic disorders, as well as anti-cancer properties. Puerariae radix (PR) is a popular natural herb and a traditional food in Asia, which has anti-thrombotic and anti-allergic properties and stimulates estrogenic activity.

Methyl thiazolyl tetrazolium assay (MTT) assay revealed a dose-dependent reduction of HT-29 cellular growth in response to puerarin treatment. Apoptosis was observed following treatments with ³ 25µM puerarin, as reflected by the appearance of the subdiploid fraction and NDA fragmentations. Puerarin also affects the expression of apoptosis-associated genes, revealing an increase of bax and decreases of c-myc and bcl-2.

Finally, puerarin treatment significantly increased the activation of caspase-3, a key executioner of apoptosis. These findings indicate that puerarin may act as a chemo-preventive and/or chemotherapeutic agent in colon cancer cells by reducing cell viability and inducing apoptosis (Li, et al., 2006).

Induces Apoptosis, Breast Cancer

Puerarin exhibits a dose-dependent inhibition of cell growth in HS578T, MDA-MB-231, and MCF-7 cell lines. Results from cell-cycle distribution and apoptosis assays revealed that puerarin induced cell apoptosis through a caspase-3-dependent pathway and mediated cell-cycle arrest in the G2/M phase. It is therefore suggested that puerarin may act as a chemo-preventive and/or chemotherapeutic agent against breast cancer by reducing cell viability and inducing apoptosis (Lin et al., 2009).

Breast Cancer, MDR

Purearin down-regulates MDR1 expression in MCF-7/adriamycin (MCF-7/adr), a human breast MDR cancer cell line. Multi-drug resistance (MDR) is a major obstacle in cancer chemotherapy and its inhibition is an effective way to reverse cancer drug resistance. Puerarin treatment significantly inhibited MDR1 expression, MDR1 mRNA and MDR1 promoter activity in MCF-7/adr cells. The suppression of MDR1 was accompanied by partial recovery of intracellular drug accumulation, leading to increased toxicity of adriamycin and fluorescence of rhodamine 123, indicating that puerarin reversed the MDR phenotype by inhibiting the drug efflux function of MDR1. Puerarin stimulated AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase and glycogen synthase kinase-3beta phosphorylation, but puerarin decreased cAMP-responsive element-binding protein phosphorylation.

The puerarin-induced suppression of MDR1 expression was reduced by AMPK inhibitor (compound C). Furthermore, both MDR1 protein expression and the transcriptional activity of cAMP-responsive element (CRE) were inhibited by puerarin and protein kinase A/CRE inhibitor (H89). Taken together, these results suggested that puerarin down-regulated MDR1 expression via nuclear factor kappa-B and CRE transcriptional activity-dependent up-regulation of AMPK in MCF-7/adr cells (Hien et al., 2010).

Acute Myeloid Leukemia (AML)

The results showed that a certain concentration of puerarin (PR) could inhibit the proliferation of these four cell lines effectively in time-and dose-dependent manners, and the intensity of inhibition on four kinds of acute myeloid leukemia (AML) cell lines was from high to low as follows: NB4>Kasumi-1>U937>HL-60. Meanwhile, PR could also change cycle process, cell proportion in G1/G0 phase decreased, cells in S phase increased and Sub-diploid peak also appeared. It is concluded that PR can selectively inhibit the proliferation of four AML cell lines and block cell-cycle process, especially for NB4 cells (Shao et al., 2010).

Aromatase Inhibition

Aromatase P450 (P450 (arom)) is overexpressed in endometriosis, endometrial cancers and uterine fibroids. With weak estrogen agonists/antagonists and some other enzymatic activities, isoflavones are increasingly advocated as a natural alternative to estrogen replacement therapy (ERT) and are available as dietary supplements. Puerarin is a major isoflavonoid compound isolated from Pueraria lobata (ge gen).

Yu et al. (2008) found that puerarin exerted a time-course effect on the inhibition of c-jun mRNA, which parallelled that of P450(arom). The suppression of P450(arom) expression and activity by puerarin treatment may associate with the down-regulation of transcription factor AP-1 or c-jun.

References

Hien TT, Kim HG, Han EH, Kang KW, Jeong HG. (2010). Molecular mechanism of suppression of MDR1 by puerarin from Pueraria lobata via NF- κ B pathway and cAMP-responsive element transcriptional activity-dependent up-regulation of AMP-activated protein kinase in breast cancer MCF-7/adr cells. Mol Nutr Food Res, 54(7):918-28. doi: 10.1002/mnfr.200900146.

Lin YJ, Hou YC, Lin CH, et al. (2009). Puerariae radix isoflavones and their metabolites inhibit growth and induce apoptosis in breast cancer cells. Biochemical and Biophysical Research Communications, 378(4):683-8. doi:10.1016/j.bbrc.2008.10.178

Shao HM, Tang YH, Jiang PJ, et al. (2010). Inhibitory effect of flavonoids of puerarin on proliferation of different human acute myeloid leukemia cell lines in vitro. Zhongguo Shi Yan Xue Ye Xue Za Zhi, 18(2):296-9.

Yu C, Li Y, Chen H, Yang S, Xie G. (2008). Decreased expression of aromatase in the Ishikawa and RL95-2 cells by the isoflavone, puerarin, is associated with inhibition of c-jun expression and AP-1 activity. Food Chem Toxicol, 46(12):3671-6. doi: 10.1016/j.fct.2008.09.045.

Yu Z, Li WJ. (2006). Induction of apoptosis by puerarin in colon cancer HT-29 cells. Cancer Letters, 238(1):53-60.

Cancer:
Lung, breast, prostate, leukemia, colorectal., esophageal., ovarian, myeloma, pancreatic, stomach, uterine

Action: Anti-angiogenic, chemo-sensitizer, multi-drug resistance reversal., anti-inflammatory, anxiolytic, anti-depressant, inhibits VEGF, anti-metastatic, synergistic effects with other cancer treatments

Honokiol is a phenolic compound purified from plants of the Magnolia genus, including Magnolia officinalis (Rehder & Wilson) and Magnolia grandiflora (L.), that exhibits anti-cancer effects in experimental models with various types of cancer cells, including esophageal., ovarian, breast, and lung cancer, as well as myeloma and leukemia. It is speculated that this compound causes cancer cell death in part through targeting mitochondria (Munroe et al., 2007; Chen et al., 2009; Fried & Arbiser, 2009).

Inhibits Angiogenesis, MDR, Anti-inflammatory, Inhibits VEGF

Honokiol is one of two dominant biphenolic compounds isolated from Magnolia spp. bark, and is the most widely researched active constituent of the bark. In vivo studies suggest that honokiol's greatest value is in its multiple anti-cancer actions. In vitro research suggests honokiol has potential to enhance current anti-cancer regimens by inhibiting angiogenesis, promoting apoptosis, providing direct cytotoxic activity, down-regulating cancer cell signaling pathways, regulating genetic expression, enhancing the effects of specific chemotherapeutic agents, radio-sensitizing cancer cells to radiation therapy, and inhibiting multi-drug resistance.

Honokiol also shows potential in preventive health by reducing inflammation and oxidative stress, providing neurological protection, and regulating glucose; in mental illness by its effects against anxiety and depression; and in helping regulate stress response signaling. Its anti-microbial effects demonstrate potential for partnering with anti-viral/antibiotic therapy, and treating secondary infections.

Honokiol may occupy a distinct therapeutic niche because of its unique characteristics: the ability to cross the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB), high systemic bioavailability, and its actions on a multiplicity of signaling pathways and genomic activity. There is a need for research on honokiol to progress to human studies and on into clinical use.

The preclinical research on honokiol's broad-ranging capabilities shows its potential as a therapeutic compound for numerous solid and hematological cancers, including its effectiveness in combating multi-drug resistance (MDR) and its synergy with other anti-cancer therapies. Research thus far shows no toxicity or serious adverse effects in animal models.

Honokiol has also been shown to inhibit spread of cancer cells through the lymph system by inhibiting one of the primary pathways involved in growth stimulation related to vascular endothelial growth factor (VEGF) (Wen et al., 2009).

Inhibits Angiogenesis, Gastric Cancer

A 2012 in vivo study in PLoS One showed that honokiol, by inhibiting angiogenic pathways such as STAT-3, dampened peritoneal dissemination of gastric cancer in mice (5 mg/kg delivered intraperitoneally) (Liu et al., 2012).

Induces Apoptosis; Leukemia

Honokiol induces cell apoptosis in several cell lines, such as leukemia cell lines HL-60, colon cancer cell lines RKO, lung cancer cell lines A549 and CH27 (Hirano et al., 1994; Wang et al., 2004; Hibasami et al., 1998; Konoshima et al., 1991;Yang et al., 2002; Kong et al., 2005). It also has remarkable in vivo anti-tumor activities in tumor mouse models (Bai et al., 2003). Honokiol has demonstrated potent anti-angiogenic and anti-tumor properties against aggressive angiosarcoma by blocking of VEGF-induced VEGF receptor 2 autophosphorylation (Konoshima et al., 1991; Yang et al., 2002).

MDR

Honokiol has also been found to down-regulate the expression of P-glycoprotein at mRNA and protein levels in MCF-7/ADR, a human breast MDR cancer cell line. The down-regulation of P-glycoprotein is accompanied with a partial recovery of the intracellular drug accumulation (Xu et al., 2006).

Prostate Cancer

In addition, it has been shown that prostate cancer cells that failed to respond to hormone withdrawal responded to honokiol-induced apoptosis. It was found to significantly induce death in cells surrounding primary and metastatic prostate cancers, the prostate stromal fibroblasts, marrow stromal cells, and bone marrow-associated endothelial cells. Honokiol is hence a promising nontoxic agent that could be used as an adjuvant with low-dose docetaxel for the treatment of hormone-refractory prostate cancer and its distant bone metastases (Shigemura et al., 2007).

Anti-metastatic

Honokiol inhibited the activity of MMP-9, which may be responsible, in part, for the inhibition of tumor cell invasiveness (Nagase et al., 2001).

Breast Cancer

The development of more targeted and low toxic drugs from traditional Chinese medicines for breast cancer are needed due to most of the anti-breast cancer drugs often being limited because of drug resistance and serious adverse reactions. Results have shown that honokiol inhibited the rate of breast cancer MDA-MB-231 cell growth (Nagalingam et al., 2012).

Synergistic Effects with Other Cancer Treatments

One of the most promising benefits of honokiol is its ability to synergize with other cancer treatments. Clinical trials are desperately needed to validate the potential synergy that has been demonstrated in vitro and in vivo.

Chemotherapy

• A 2013 in vitro study published in the International Journal of Oncology showed that honokiol synergized chemotherapy drugs in Multi-drug-resistant breast cancer (Tian et al., 2013). A 2011 in vitro study published in PLoS One found that honokiol enhanced the apoptotic effects of the anti-cancer drug gemcitabine against pancreatic cancer (Arora et al., 2011).

• In vivo research published in Oncology Letters in 2011 found honokiol enhanced the action of cisplatin against colon cancer (Cheng et al., 2011).

• A 2010 in vitro study from the Journal of Biological Regulators and Homeostatic Agents showed that honokiol resensitized cancer cells to doxorubicin in Multi-drug-resistant uterine cancer (Angelini et al., 2010).

• A 2010 in vitro study published in Toxicology Mechanisms and Methods showed honokiol performed synergistically with the drug imatinib against human leukemia cells (Wang et al., 2010).

• 2008 in vivo research published in the International Journal of Gynecological Cancer showed honokiol to potentiate the activity of cisplatin in murine models of ovarian cancer (Liu et al., 2008).

• 2005 in vitro research published in Blood showed honokiol enhanced the cytotoxicity induced by fludarabine, cladribine, and chlorambucil, indicating it is a potent inducer of apoptosis in B-CLL cells (Battle et al., 2005).

Radiation treatment

• 2012 in vitro research published in Molecular Cancer Therapeutics showed that honokiol was able to sensitize cancer cells to radiation treatments (Ponnurangam et al., 2012).

• A 2011 in vitro study published in American Journal of Physiology Gastrointestinal and Liver Physiology showed honokiol sensitized treatment-resistant colon cancer cells to radiation therapy (He et al., 2011).

Inhibition of multi-drug resistance

Honokiol has been shown to interact with genes that are involved with mechanisms of drug efflux, thus reversing MDR in experimental models. The exact mechanisms of action in this regard are thought to be related to effects of blocking of NF-kB activity, but other mechanisms may also be involved (Xu et al., 2006).

References

Angelini A, Di Ilio C, Castellani ML, Conti P, Cuccurullo F. (2010). Modulation of Multi-drug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin-resistant sarcoma cells (MES-SA/DX-5): Implications for natural sedatives as chemosensitizing agents in cancer therapy. Journal of Biological Regulators & Homeostatic Agents, 24(2). 197-205.

Arora S, Bhardwaj A, Srivastava SK, et al. (2011). Honokiol arrests Cell-cycle, induces apoptosis, and potentiates the cytotoxic effect of gemcitabine in human pancreatic cancer cells. PLoS One, 6(6), e21573. doi: 10.1371/journal.pone.0021573.

Bai X, Cerimele F, Ushio-Fukai M, et al. (2003). Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo. J Biol Chem, 278: 35501–7.

Battle TE, Arbiser J, Frank DA. (2005). The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood, 106(2), 690-697.

Chen G, Izzo J, Demizu Y, et al. (2009). Different redox states in malignant and nonmalignant esophageal epithelial cells and differential cytotoxic responses to bile acid and honokiol. Antioxid. Redox Signal., 11(5):1083–1095

Cheng N, Xia T, Han Y, et al. (2001). Synergistic anti-tumor effects of liposomal honokiol combined with cisplatin in colon cancer models. Oncology Letters, 2(5), 957-962.

Eliaz I. (2013). Honokiol research review: A promising extract with multiple applications. Natural Medicine Journal., 5(7).

Fried LE, Arbiser JL. (2009). Honokiol, a multifunctional anti-angiogenic and anti-tumor agent. Antioxid. Redox Signal., 1(5):1139–1148. doi: 10.1089/ARS.2009.2440.

He Z, Subramaniam D, Ramalingam S, et al. (2011). Honokiol radiosensitizes colorectal cancer cells: enhanced activity in cells with mismatch repair defects. American Journal of Physiology: Gastrointest and Liver Physiology, 301(5):G929-937.

Hibasami H, Achiwa Y, Katsuzaki H, et al. (1998). Honokiol induces apoptosis in human lymphoid leukemia Molt 4B cells. Int J Mol Med, 2:671–3.

Hirano T, Gotoh M, Oka K. (1994). Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci, 55:1061–9.