Category Archives: anxiolytic

anti-inflammatory, anti-oxidant, anxiolytic, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Chapter 7 Isolates and Cancer Research, COX-2, COX-2 down-regulation, FasL, G0/G1, G1, Gastric cancer or Stomach cancer, growth-inhibitory, HT-29, IL-1, IL-6, induces apoptosis, inflammation, Nitric Oxide, p27, Paeonia suffruticosa, S, TNF

Paenol

April 20, 2014 brian

Cancer: Gastric

Action: Attenuates nephrotoxicity, anti-inflammatory, anti-oxidant, inhibits TNF- α , induces apoptosis, COX-2 down-regulation

Inhibits TNF- α

Moutan Cortex, the root bark of Paeonia suffruticosa Andrews, has been used extensively as a traditional medicine for treatment of various diseases such as atherosclerosis, infection, and inflammation. Previous studies have revealed that the extracts of Moutan Cortex can inhibit nitric oxide and TNF- α in activated mouse peritoneal macrophages (Chung et al., 2007).

A variety of compounds including paeonoside, paeonolide, apiopaeonoside, paeoniflorin, oxypaeoniflorin, benzoyloxypaeoniflorin, benzoylpaeoniflorin, paeonol, and sugars have been identified in Moutan Cortex (Chen et al., 2006).

Attenuates Nephrotoxicity

Paeonol, a major compound of Moutan Cortex, has been found to attenuate cisplatin-induced nephrotoxicity in mice. Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug.

Balb/c mice (6 to 8 w of age, weighing 20 to 25 g) were administered with Moutan Cortex (300 mg/kg) or paeonol (20 mg/kg) once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg) intraperitoneally.

The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of pro-inflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin (Lee et al., 2013).

Paeonol, a major phenolic component of Moutan Cortex, has various biological activities such as anti-aggregatory, anti-oxidant, anxiolytic-like, and anti-inflammatory functions (Ishiguro et al., 2006). In this study, paeonol treatment significantly reduced the elevated levels of serum creatinine and BUN. In addition, the role of pro-inflammatory cytokines in cisplatin-induced acute renal failure has been well documented (Faubel et al., 2007; Ramesh & Reeves, 2002), and elevation of the pro-inflammatory cytokines TNF-α and IL-1β as well as that of IL-6 has been demonstrated in humans with acute renal failure (Simmons et al., 2004).

Apoptosis-inducing & Gastric Cancer

Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo. In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression (Li et al., 2010).

COX-2 Down-regulation

One of the apoptotic mechanisms of paeonol is down-regulation of COX-2. p27 is up-regulated simultaneously and plays an important part in controlling cell proliferation and is a crucial factor in the Fas/FasL apoptosis pathway. Cell proliferation was inhibited by different concentrations of paeonol. By immunocytochemical staining, Ye et al. (2009) found that HT-29 cells treated with paeonol (0.024-1.504 mmol/L) reflected reduced expression of COX-2 and increased expression of p27 in a dose-dependent manner. RT-PCR showed that paeonol down-regulated COX-2 and up-regulated p27 in a dose- and time-dependent manner in HT-29 cells.

References

Chen G, Zhang L, Zhu Y. (2006). Determination of glycosides and sugars in moutan cortex by capillary electrophoresis with electrochemical detection. Journal of Pharmaceutical and Biomedical Analysis, 41(1):129–134.

Chung HS, M. Kang, C. Cho et al. (2007). Inhibition of nitric oxide and tumor necrosis factor-alpha by moutan cortex in activated mouse peritoneal macrophages. Biological and Pharmaceutical Bulletin, 30(5):912–916.

Faubel F, Lewis EC, Reznikov L et al. (2007). Cisplatin-induced acute renal failure is associated with an increase in the cytokines interleukin (IL)-1 β , IL-18, IL-6, and neutrophil infiltration in the kidney. Journal of Pharmacology and Experimental Therapeutics, 322(1):8–15.

Ishiguro K, Ando T, Maeda O et al. (2006). Paeonol attenuates TNBS-induced colitis by inhibiting NF- κ B and STAT1 transactivation. Toxicology and Applied Pharmacology, 217(1):35–42.

Lee HJ, Lee GY, Kim Hs, Bae Hs. (2013). Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice. Evidence-Based Complementary and Alternative Medicine, 2013(2013), http://dx.doi.org/10.1155/2013/310989

Li N, Fan LL, Sun GP, et al. (2010). Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. World J Gastroenterol., 16(35):4483-90.

Ramesh G, Reeves wb. (2002). TNF- α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. Journal of Clinical Investigation, 110(6):835–842.

Simmons EM, Himmelfarb j, Sezer MT et al. (2004). Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney International, 65(4):1357–1365.

Ye JM, Deng T, Zhang JB. (2009) Influence of paeonol on expression of COX-2 and p27 in HT-29 cells. World J Gastroenterol, 15(35):4410-4.

AhR, Akt, angiogenesis, Anti-angiogenic, anti-apoptotic, Anti-cancer, Anti-cancer effect, anti-inflammatory, anti-oxidant, anti-proliferative, anti-proliferative effect, anti-tumor, anxiolytic, apoptosis, Apoptotic, BAX, Bcl-2, Breast cancer, CAL-27, FaDu, cardio-protective, cardio-protective against Doxorubicin, cardiovascular disease, Causes cell-cycle arrest, CDK4, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, Cytostatic, cytotoxic, G1, G2/M, Head and neck cancer, Hep G2,Hep 3B and SK-Hep1, HIF, HL-60/ADR, IL-6, inflammation, iNOS, JNK, MCF-7, T-47D, MDA-MB-231, Nitric Oxide, Oral cancer, Ovarian cancer, Ovarian cancer cell lines, OVCAR-3, CP-70, IOSE-364, p53, Prostate cancer, ROS, S, VEGF, VEGF, XIAP

Baicalin & Baicalein

March 28, 2014 brian

Cancer:
Myeloma, liver, colorectal., breast, prostate, oral., hepatoma, ovarian

Action: Anti-cancer, cardiovascular disease, cytostatic, cardio-protective against Doxorubicin, anti-inflammatory, angiogenesis

Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants (including Scutellaria radix, Scutellaria rivularis (Benth.); Scutellaria baicalensis (Georgi) and Scutellaria lateriflora (L.)) are thought to have anti-oxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. In particular, Scutellaria baicalensis is one of the most popular and multi-purpose herbs used in China traditionally for treatment of inflammation, hypertension, cardiovascular diseases, and bacterial and viral infections (Ye et al., 2002; Zhang et al., 2011a).

Anti-cancer

Accumulating evidence demonstrates that Scutellaria also possesses potent anti-cancer activities. The bioactive components of Scutellaria have been confirmed to be flavones, wogonin, baicalein and baicalin. These phytochemicals are not only cytostatic but also cytotoxic to various human tumor cell lines in vitro and inhibit tumor growth in vivo. Most importantly, they show almost no or minor toxicity to normal epithelial and normal peripheral blood and myeloid cells. The anti-tumor functions of these flavones are largely due to their abilities to scavenge oxidative radicals, to attenuate NF-kappaB activity, to inhibit several genes important for regulation of the cell-cycle, to suppress COX-2 gene expression and to prevent viral infections (Li, 2008).

Multiple Myeloma

In the search for a more effective adjuvant therapy to treat multiple myeloma (MM), Ma et al. (2005) investigated the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells. HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3.

Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin. Baicalein as well as baicalin suppressed the survival in vitro of MPC-1- immature myeloma cells rather than MPC-1+ myeloma cells from myeloma patients.

Baicalein inhibited the phosphorylation of IkB-alpha, which was followed by decreased expression of the IL-6 and XIAP genes and activation of caspase-9 and caspase-3. Therefore, HLJDT and Scutellaria radix have an anti-proliferative effect on myeloma cells, especially MPC-1- immature myeloma cells, and baicalein may be responsible for the suppressive effect of Scutellaria radix by blocking IkB-alpha degradation (Ma, 2005).

Hepatoma

The effects of the flavonoids from Scutellaria baicalensis Georgi (baicalein, baicalin and wogonin) in cultured human hepatoma cells (Hep G2, Hep 3B and SK-Hep1) were compared by MTT assay and flow cytometry. All three flavonoids dose-dependently decreased the cell viabilities accompanying the collapse of mitochondrial membrane potential and the depletion of glutathione content. However, the influence of baicalein, baicalin or wogonin on cell-cycle progression was different.

All three flavonoids resulted in prominent increase of G2/M population in Hep G2 cells, whereas an accumulation of sub G1 (hypoploid) peak in Hep 3B cells was observed. In SK-Hep1 cells, baicalein and baicalin resulted in a dramatic boost in hypoploid peak, but wogonin mainly in G1 phase accumulation. These data, together with the previous findings in other hepatoma cell lines, suggest that baicalein, baicalin and wogonin might be effective candidates for inducing apoptosis or inhibiting proliferation in various human hepatoma cell lines (Chang, 2002).

Long dan xie gan tang (pinyin) is one of the most commonly used herbal formulas by patients with chronic liver disease in China. Accumulated anecdotal evidence suggests that Long dan tang may have beneficial effects in patients with hepatocellular carcinoma. Long dan tang is comprised of five herbs: Gentiana root, Scutellaria root, Gardenia fruit, Alisma rhizome, and Bupleurum root. The cytotoxic effects of compounds from the five major ingredients isolated from the above plants, i.e. gentiopicroside, baicalein, geniposide, alisol B acetate and saikosaponin-d, were investigated, respectively, on human hepatoma Hep3B cells..

Interestingly, baicalein by itself induced an increase in H(2)O(2) generation and the subsequent NF-kappaB activation; furthermore, it effectively inhibited the transforming growth factor-beta(1) (TGF-beta(1))-induced caspase-3 activation and cell apoptosis. Results suggest that alisol B acetate and saikosaponin-d induced cell apoptosis through the caspase-3-dependent and -independent pathways, respectively. Instead of inducing apoptosis, baicalein inhibits TGF-beta(1)-induced apoptosis via increase in cellular H(2)O(2) formation and NF-kappaB activation in human hepatoma Hep3B cells (Chou, Pan, Teng & Guh, 2003).

Ovarian Cancer

Ovarian cancer is one of the primary causes of death for women all through the Western world. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45-55 µM for baicalin and 25-40 µM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 µM for baicalin and 68 µM for baicalein.

Baicalin decreased expression of VEGF (20 µM), cMyc (80 µM), and NFkB (20 µM); baicalein decreased expression of VEGF (10 µM), HIF-1α (20 µM), cMyc (20 µM), and NFkB (40 µM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB.

Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers (Chen, 2013).

Breast Cancer

Baicalin was found to be a potent inhibitor of mammary cell line MCF-7 and ductal breast epithelial tumor cell line T-47D proliferation, as well as having anti-proliferative effects on other cancer types such as the human head and neck cancer epithelial cell lines CAL-27 and FaDu. Overall, baicalin inhibited the proliferation of human breast cancer cells and CAL-27 and FaDu cells with effective potency (Franek, 2005).

Breast Cancer, Cell Invasion

The effect of Baicalein on cell viability of the human breast cancer MDA-MB-231 cell line was tested by MTT. 50, 100 µmol·L-1 of Baicalein inhibited significantly cell invasion(P0.01) and migration(P0.01) compared with control groups. The inhibitory rates were 50% and 77% in cell migration and 15% and 44% in cell invasion, respectively. 50 µmol·L-1 of Baicalein significantly inhibited the level of MMP 2 expression. 100 µmol·L-1 of Baicalein significantly inhibited the level of MMP 9 and uPA expressions.

Baicalein inhibits invasion and migration of MDA-MB-231 cells. The mechanisms may be involved in the direct inhibition of cell invasion and migration abilities, and the inhibition of MMP 2, MMP 9, and uPA expressions (Wang et al., 2010).

The proliferation of MDA-MB-231 cell line human breast adenocarcinoma was inhibited by baicalin in a dose-and time-dependent manner and the IC50 was 151 µmol/L. The apoptotic rate of the baicalin-treated MDA-MB-231 cells increased significantly at 48 hours. Flow cytometer analysis also revealed that most of the baicalin-treated MDA-MB-231 cells were arrested in the G2/M phase. Typically apoptotic characteristics such as condensed chromatin and apoptotic bodies were observed after being treated with baicalin for 48 hours.

The results of RT-PCR showed that the expression of bax was up-regulated; meanwhile, the expression of bcl-2 was down-regulated. Baicalin could inhibit the proliferation of MDA-MB-231 cells through apoptosis by regulating the expression of bcl-2, bax and intervening in the process of the cell-cycle (Zhu et al., 2008).

Oral Cancer

As an aryl hydrocarbon receptor (AhR) ligand, baicalein at high concentrations blocks AhR-mediated dioxin toxicity. Because AhR had been reported to play a role in regulating the cell-cycle, it is suspected that the anti-cancer effect of baicalein is associated with AhR. The molecular mechanism involved in the anti-cancer effect of baicalein in oral cancer cells HSC-3 has been investigated, including whether such an effect would be AhR-mediated. Results revealed that baicalein inhibited cell proliferation and increased AhR activity in a dose-dependent manner. Cell-cycle was arrested at the G1 phase and the expression of CDK4, cyclin D1, and phosphorylated retinoblastoma (pRb) was decreased.

When cells were pre-treated with LiCl, the inhibitor of GSK-3β, the decrease of cyclin D1 was blocked and the reduction of pRb was recovered. The data indicates that in HSC-3 the reduction of pRb is mediated by baicalein both through activation of AhR and facilitation of cyclin D1 degradation, which causes cell-cycle arrest at the G1 phase, and results in the inhibition of cell proliferation (Cheng, 2012).

Anti-inflammatory

Baicalin has also been examined for its effects on LPS-induced nitric oxide (NO) production and iNOS and COX-2 gene expressions in RAW 264.7 macrophages. The results indicated that baicalin inhibited LPS-induced NO production in a concentration-dependent manner without a notable cytotoxic effect on these cells. The decrease in NO production was consistent with the inhibition by baicalin of LPS-induced iNOS gene expression (Chen, 2001)

Angiogenesis Modulation

The modulation of angiogenesis is one possible mechanism by which baicalin may act in the treatment of cardiovascular diseases. This may be elucidated by investigating the effects of baicalin on the expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis. The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1alpha (HIF-1alpha).

Their ability to induce VEGF expression was suppressed once ERRalpha expression was knocked down by siRNA, or ERRalpha-binding sites were deleted in the VEGF promoter. It was also found that both agents stimulated cell migration and vessel sprout formation from the aorta. These results therefore implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERRalpha pathway (Zhang, 2011b).

Colon Cancer

The compounds of baicalein and wogonin, derived from the Chinese herb Scutellaria baicalensis, were studied for their effect in suppressing the viability of HT-29 human colon cancer cells. Following treatment with baicalein or wogonin, several apoptotic events were observed, including DNA fragmentation, chromatin condensation and increased cell-cycle arrest at the G1 phase. Baicalein and wogonin decreased Bcl-2 expression, whereas the expression of Bax was increased in a dose-dependent manner when compared to the control.

The results indicated that baicalein induced apoptosis via Akt activation, in a p53-dependent manner, in HT-29 colon cancer cells. Baicalein may serve as a chemo-preventive, or therapeutic, agent for HT-29 colon cancer (Kim et al., 2012).

Cardio-protective

The cardiotoxicity of doxorubicin limits its clinical use in the treatment of a variety of malignancies. Previous studies suggest that doxorubicin-associated cardiotoxicity is mediated by reactive oxygen species (ROS)-induced apoptosis. Baicalein attenuated phosphorylation of JNK induced by doxorubicin. Co-treatment of cardiomyocytes with doxorubicin and JNK inhibitor SP600125 (10 µM; 24 hours) reduced JNK phosphorylation and enhanced cell survival., suggesting that the baicalein protection against doxorubicin cardiotoxicity was mediated by JNK activation. Baicalein adjunct treatment confers anti-apoptotic protection against doxorubicin-induced cardiotoxicity without compromising its anti-cancer efficacy (Chang et al., 2011).

Prostate Cancer

There are four compounds capable of inhibiting prostate cancer cell proliferation in Scutellaria baicalensis: baicalein, wogonin, neobaicalein, and skullcapflavone. Comparisons of the cellular effects induced by the entire extract versus the four-compound combination produced comparable cell-cycle changes, levels of growth inhibition, and global gene expression profiles (r(2) = 0.79). Individual compounds exhibited anti-androgenic activities with reduced expression of the androgen receptor and androgen-regulated genes. In vivo, baicalein (20 mg/kg/d p.o.) reduced the growth of prostate cancer xenografts in nude mice by 55% at 2 weeks compared with placebo and delayed the average time for tumors to achieve a volume of approximately 1,000 mm(3) from 16 to 47 days (P < 0.001).

Most of the anti-cancer activities of S. baicalensis can be recapitulated with four purified constituents that function in part through inhibition of the androgen receptor signaling pathway (Bonham et al., 2005)

Cancer: Acute lymphocytic leukemia, lymphoma and myeloma

Action: Cell-cycle arrest, induces apoptosis

Scutellaria baicalensis (S.B.) is a widely used Chinese herbal medicine. S.B inhibited the growth of acute lymphocytic leukemia (ALL), lymphoma and myeloma cell lines by inducing apoptosis and cell cycle arrest at clinically achievable concentrations. The anti-proliferative effectwas associated with mitochondrial damage, modulation of the Bcl family of genes, increased level of the CDK inhibitor p27KIP1 and decreased level of c-myc oncogene. HPLC analysis of S.B. showed it contains 21% baicalin and further studies confirmed it was the major anti-cancer component of S.B. Thus, Scutellaria baicalensis should be tested in clinical trials for these hematopoietic malignancies (Kumagai et al., 2007).

References

Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson PS. (2005). Characterization of chemical constituents in Scutellaria baicalensis with antiandrogenic and growth-inhibitory activities toward prostate carcinoma. Clin Cancer Res, 11(10):3905-14.

Chang WH Chen CH Lu FJ. (2002). Different Effects of Baicalein, Baicalin and Wogonin on Mitochondrial Function, Glutathione Content and cell-cycle Progression in Human Hepatoma Cell Lines. Planta Med, 68(2):128-32. doi: 10.1055/s-2002-20246

Chang WT, Li J, Huang HH, et al. (2011). Baicalein protects against doxorubicin-induced cardiotoxicity by attenuation of mitochondrial oxidant injury .and JNK activation. J Cell Biochem. doi: 10.1002/jcb.23201.

Chen J, Li Z, Chen AY, Ye X, et al. (2013). Inhibitory effect of baicalin and baicalein on ovarian cancer cells. Int J Mol Sci, 14(3):6012-25. doi: 10.3390/ijms14036012.

Chen YC, Shen SC, Chen LG, Lee TJ, Yang LL. (2001). Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem Pharmacol,61(11):1417-27. doi:10.1016/S0006-2952(01)00594-9

Cheng YH, Li LA, Lin P, et al. (2012). Baicalein induces G1 arrest in oral cancer cells by enhancing the degradation of cyclin D1 and activating AhR to decrease Rb phosphorylation. Toxicol Appl Pharmacol, 263(3):360-7. doi: 10.1016/j.taap.2012.07.010.

Chou CC, Pan SL, Teng CM, & Guh JH. (2003). Pharmacological evaluation of several major ingredients of Chinese herbal medicines in human hepatoma Hep3B cells. European Journal of Pharmaceutical Sciences, 19(5), 403-12.

Franek KJ, Zhou Z, Zhang WD, Chen WY. (2005). In vitro studies of baicalin alone or in combination with Salvia miltiorrhiza extract as a potential anti-cancer agent. Int J Oncol, 26(1):217-24.

Kim SJ, Kim HJ, Kim HR, et al. (2012). Anti-tumor actions of baicalein and wogonin in HT-29 human colorectal cancer cells. Molecular Medicine Reports, 6(6):1443-1449. doi: 10.3892/mmr.2012.1085.

Li-Weber M. (2009). New therapeutic aspects of flavones: The anti-cancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev, 35(1):57-68. doi: 10.1016/j.ctrv.2008.09.005.

Ma Z, Otsuyama K, Liu S, et al. (2005). Baicalein, a component of Scutellaria radix from Huang-Lian-Jie-Du-Tang (HLJDT), leads to suppression of proliferation and induction of apoptosis in human myeloma cells. Blood, 105(8):3312-8. doi:10.1182/blood-2004-10-3915.

Wang Xf, Zhou Qm, Su Sb. (2010). Experimental study on Baicalein inhibiting the invasion and migration of human breast cancer cells. Zhong Guo Yao Li Xue Tong Bao, 26(6): 745-750.

Zhang XW, Li WF, Li WW, et al. (2011a). Protective effects of the aqueous extract of Scutellaria baicalensis against acrolein-induced oxidative stress in cultured human umbilical vein endothelial cells. Pharm Biol, 49(3): 256–261. doi:10.3109/13880209.2010.501803.

Ye F, Xui L, Yi J, Zhang, W, Zhang DY. (2002). Anti-cancer activity of Scutellaria baicalensis and its potential mechanism. J Altern Complement Med, 8(5):567-72.

Zhang K, Lu J, Mori T, et al. (2011b). Baicalin increases VEGF expression and angiogenesis by activating the ERR{alpha}/PGC-1{alpha} pathway.[J]. Cardiovascular Research, 89(2):426-435.

Zhu Gq, Tang Lj, Wang L, Su Jj, et al. (2008). Study on Baicalin Induced Apoptosis of Human Breast Cancer Cell Line MDA-MB-231. An Hui Zhong Yi Xue Yuan Xue Bao, 27(2):20-23

Kumagai T, et al. (2007) Scutellaria baicalensis, a herbal medicine: Anti-proliferative and apoptotic activity against acute lymphocytic leukemia, lymphoma and myeloma cell lines. Leukemia Research 31 (2007) 523-530

A549 and CH27, angiogenesis, Anti-angiogenic, Anti-cancer, anti-depressant, anti-inflammatory, Anti-metastatic, anti-tumor, Antibiotic, anxiolytic, apoptosis, Apoptotic, B-CLL, Breast cancer, Chapter 7 Isolates and Cancer Research, Chemo-sensitizer, Chemotherapy, Colon Cancer or Colorectal cancer, cytotoxic, Depression or Anxiety, HL-60, induces apoptosis, inflammation, inhibits angiogenesis, inhibits VEGF, Lung cancer, MCF-7/ADR, MDR, Multi-Drug Resistance, Multi-drug resistance, Multi-drug resistance reversal, Ovarian cancer, Pancreatic cancer, Prostate cancer, radio-sensitizing, RKO, Sarcoma, STAT, Uterine cancer, VEGF, VEGF

Honokiol (See also Injectables)

March 27, 2014 brian

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.