Category Archives: STAT

angiogenesis, Anti-angiogenesis, Anti-angiogenic, anti-tumor, apoptosis, Bladder cancer, Breast cancer, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-preventive, Cip1/p21, Colon Cancer or Colorectal cancer, EGFR, EMT, epidermal growth factor receptor, ERK, ERK1, Fet, Geo, and HCT116, G1, HL-60, HT-29, Induces cell-cycle arrest, iNOS, Lung cancer, metastasis, Nitric Oxide, p21, PKC, S, Silybum marianum, STAT, STAT3, Thyroid cancer, TNF

Silibinin

Cancer:
Lung, leukemia, colorectal, thyroid, breast, bladder

Action: Anti-angiogenesis, EMT, cell-cycle arrest

Cell-cycle Arrest, Colon Cancer

Silibinin, an active constituent of milk thistle (Silybum marianum [(L.) Gaertn.]), has been reported to inhibit proliferation and induce cell-cycle arrest of human colon cancer cells, Fet, Geo, and HCT116 (Hogan et al., 2007). Silibinin Up-regulates the expression of cyclin-dependent kinase inhibitors and induces cell-cycle arrest and apoptosis in human colon carcinoma HT-29 cells (Agarwal et al., 2003). Also in HT-29 cells, treatment with beta-escin, a principal component of horse chestnut, tinduces growth arrest at the G1-S phase together with an induction of Cip1/p21 and an associated reduction in the phosphorylation of retinoblastoma protein (Patlolla et al., 2006).

Lung Cancer

Silibinin also has anti-angiogenic effects on lung adenocarcinomas in vitro, as it strongly decreased both tumor number and tumor size (an anti-tumor effect that correlates with reduced anti-angiogenic activity) (Tyagi et al., 2009). Further, silibinin inhibits mouse lung tumorigenesis in vivo, in part by targeting tumor microenvironment. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) can be pro- or anti-tumorigenic, but in lung cancer cell lines they induce pro-inflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Accordingly, the mechanism of silibinin action was examined on TNF-α + IFN-γ (hereafter referred as cytokine mixture) elicited signaling in tumor-derived mouse lung epithelial LM2 cells.

Both signal transducers and activators of the transcription (STAT)3 (tyr705 and ser727) and STAT1 (tyr701) were activated within 15 min of cytokine mixture exposure, while STAT1 (ser727) activated after 3 h. Cytokine mixture also activated Erk1/2 and caused an increase in both COX2 and iNOS levels. Pre-treatment of cells with a MEK, NF-κB, and/or epidermal growth factor receptor (EGFR) inhibitor inhibited cytokine mixture-induced activation of Erk1/2, NF-κB, or EGFR, respectively, and strongly decreased phosphorylation of STAT3 and STAT1 and expression of COX2 and iNOS.

Together, the results show that STAT3 and STAT1 could be valuable chemo-preventive and therapeutic targets within the lung tumor microenvironment in addition to being targets within the tumor itself, and that silibinin inhibit their activation as a plausible mechanism of its efficacy against lung cancer (Tyagi et al., 2011).

Leukemia

Silibinin also affects cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Treatment of HL-60 cells with silibinin inhibited cellular proliferation and induced cellular differentiation in a dose-dependent manner.

Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKCα and PKCβ in 1,25-(OH)2D3-treated HL-60 cells. PKC and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by silibinin alone or in combination with 1,25-(OH)2D3, indicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation (Kang et al., 2001).

Thyroid Cancer, Breast Cancer

Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Matrix metalloproteinases (MMPs) play an important role in cancer metastasis, cell migration and invasion. The effects of silibinin were investigated on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. These results revealed that the levels of MMP-9 mRNA and protein expression were significantly increased by TPA but not MMP-2 in TPC-1 and MCF7 cells.

TPA-induced phosphorylation of MEK and ERK was also inhibited by silibinin. Taken together, these results suggest that silibinin suppresses TPA-induced cell migration and MMP-9 expression through the MEK/ERK-dependent pathway in thyroid and breast cancer cells (Oh et al., 2013).

Bladder Cancer

Silibinin induced apoptosis and inhibited proliferation of bladder cancer cells and metastasis. In the present study, Wu et al. (2013) utilized a novel highly metastatic T24-L cell model, and found that silibinin treatment not only resulted in the suppression of cell migration and invasion in vitro, but also decreased bladder cancer lung metastasis and prolonged animal survival in vivo. Inactivation of β-catenin/ZEB1 signaling by silibinin leads to dual-block of EMT and stemness.

Lung Cancer, EMT

Silibinin formulation might facilitate the design of clinical trials to test the administration of silibinin meglumine-containing injections, granules, or beverages in combination with EGFR TKIs in patients with EGFR-mutated NSCLC. Silibinin meglumine notably decreased the overall volumes of NSCLC tumors as efficiently as did the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Concurrent treatment with silibinin meglumine impeded the regrowth of gefitinib-unresponsive tumors, resulting in drastic tumor growth prevention.

Because the epithelial-to-mesenchymal transition (EMT) is required by a multiplicity of mechanisms of resistance to EGFR TKIs, we evaluated the ability of silibinin meglumine to impede the EMT in vitro and in vivo. Silibinin-meglumine efficiently prevented the loss of markers associated with a polarized epithelial phenotype as well as the de novo synthesis of proteins associated with the mesenchymal morphology of transitioning cells (Cuf` et al., 2013).

Breast cancer

Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day.

Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b+ Gr-1+ MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b+Gr-1+ MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment.

Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs.

References

 

Agarwal C, Singh RP, Dhanalakshmi S, et al. (2003). Silibinin Up-regulates the expression of cyclin-dependent kinase inhibitors and causes cell-cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 22:8271–8282.

 

Cufí S, Bonavia R, Vazquez-Martin A, Corominas-Faja B, et al. (2013). Silibinin meglumine, a water-soluble form of milk thistle silymarin, is an orally active anti-cancer agent that impedes the epithelial-to-mesenchymal transition (EMT) in EGFR-mutant non-small-cell lung carcinoma cells. Food Chem Toxicol, 60:360-8. doi: 10.1016/j.fct.2013.07.063.

Hogan FS, Krishnegowda NK, Mikhailova M, Kahlenberg MS. (2007). Flavonoid, silibinin, inhibits proliferation and promotes cell-cycle arrest of human colon cancer. J Surg Res, 143:58–65.

Kang SN, Lee MH, Kim KM, Cho D, Kim TS. (2001). Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochemical Pharmacology, 61(12):1487–1495

Oh SJ, Jung SP, Han J, et al. (2013). Silibinin inhibits TPA-induced cell migration and MMP-9 expression in thyroid and breast cancer cells. Oncol Rep, 29(4):1343-8. doi: 10.3892/or.2013.2252.

Patlolla JM, Raju J, Swamy MV, Rao CV. (2006). Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the Cell-cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol Cancer Ther, 5:1459–1466.

Tyagi A, Singh RP, Ramasamy K, et al. (2009). Growth Inhibition and Regression of Lung Tumors by Silibinin: Modulation of Angiogenesis by Macrophage-Associated Cytokines and Nuclear Factor-κ B and Signal Transducers and Activators of Transcription 3. Cancer Prev Res, 2(1):74-83

Tyagi A, Agarwal C, Dwyer-Nield LD, et al. (2011). Silibinin modulates TNF‐α and IFN ‐γ mediated signaling to regulate COX2 and iNOS expression in tumorigenic mouse lung epithelial LM2 cells. Molecular Carcinogenesis. doi: 10.1002/mc.20851.

Wu K, Ning Z, Zeng J, et al. (2013). Silibinin inhibits β -catenin/ZEB1 signaling and suppresses bladder cancer metastasis via dual-blocking epithelial-mesenchymal transition and stemness. Cell Signal, 25(12):2625-2633. doi: 10.1016/j.cellsig.2013.08.028.

Forghani P, Khorramizadeh MR & Waller EK. (2014) Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer. Cancer Medicine. Volume 3, Issue 2, pages 215–224, April 2014 DOI: 10.1002/cam4.186

Anti-cancer, anti-inflammatory, apoptosis, Apoptotic, Breast cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, Chemotherapy, CSC, CSCs, DNMT2, EMT, IKK, inflammation, inhibits NF-κB, JNK, p53, p65, Pro-apoptotic, promotes apoptosis, ROS, STAT, Tanacetum parthenium

Parthenolide

Cancer:
Myeloma, ovarian adenocarcinoma, breast, acute myelogenous leukemia, epithelial-to-mesenchymal transition (EMT)

Action: Anti-cancer, anti-inflammatory, inhibits NF-κB, promotes apoptosis

Inhibits NF-κB & Promotes Apoptosis

Parthenolide, a sesquiterpene lactone derived from the leaves of feverfew (Tanacetum parthenium (L.)), is considered a main bioactive component of this herb. Feverfew has been used orally or as an infusion for the treatment of migraine, arthritis, fever, and stomachache. Besides its anti-inflammatory and anti-migraine properties, parthenolide also shows anti-cancer activities in a variety of cell lines. It contains an alpha-methylene-gamma-lactone ring and an epoxide moiety which are able to interact with nucleophilic sites of biologically important molecules.

Parthenolide modulates multiple targets, thereby contributing to its various in vitro and in vivo effects. Inhibition of NF-kappaB activity, constitutive in many types of cancers via either interaction with IKK or more directly with the p65 subunit of NF-kappaB, is considered one of the main mechanisms of its action. In addition, inhibition of STAT and MAP kinase activities and the induction of sustained JNK activity as well as p53 activity via influencing MDM2 and HDAC1 levels lead to an increased susceptibility of cancer cells to chemo- and radio- therapy. At the epigenetic level, parthenolide reduces HDAC1 level and, by inhibiting DNMT2 activity, induces global hypomethylation of DNA, which can restore the expressions of some suppressor genes.

Moreover, this compound reduces the cellular level of GSH in cancer cells, followed by ROS accumulation and apoptosis. A unique property of parthenolide is its ability to induce cell death mainly in cancer cells, while sparing healthy ones and it also protects normal cells from UVB and oxidative stress. More remarkably, it seems to have the potential to target some cancer stem cells. Its wide array of biological activity and low toxicity make parthenolide a very promising drug with multi-pharmacological potential, largely dependent on the cellular context (Koprowska et al., 2010).

Multiple Myeloma

It has been shown that parthenolide is a potent anti-MM-CSC agent. Multiple myeloma (MM) is an incurable plasma cell malignancy where nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor, leaving the cancer stem cells to trigger a relapse. It demonstrated preferential toxicity toward MM-CSCs over non-tumorigenic MM cells. Addition of the bone marrow stromal compartment abrogated andrographolide activity while having no effect on parthenolide cytoxicity. It hence has anti-CSC activity in myeloma, suggesting that it has the potential to improve the survival of patients with MM by eliminating the relapse-causing MM-CSCs (Gunn et al., 2011).

Acute Myelogenous Leukemia

Parthenolide (PTL), a naturally occurring small molecule, induces robust apoptosis in primary human acute myelogenous leukemia (AML) cells and blast crisis CML (bcCML) cells while sparing normal hematopoietic cells. Furthermore, analysis of progenitor cells using in vitro colony assays, as well as stem cells using the non-obese diabetic/severe combined immunodeficient (NOD/SCID) xenograft model, show that PTL also preferentially targets AML progenitor and stem cell populations.

Notably, in comparison to the standard chemotherapy drug cytosine arabinoside (Ara-C), PTL is much more specific to leukemia cells. The molecular mechanism of PTL-mediated apoptosis is strongly associated with inhibition of nuclear factor κB (NF-κB), pro-apoptotic activation of p53, and increased reactive oxygen species (ROS) (Guzman, et al., 2005).

PTL is known to be a potent inhibitor of NF-κB (Bork et al., 1997). The mechanism of NF-κB down-regulation appears to occur via inhibition of the IKK complex. Guzman et al. (2005) observed strong inhibition of NF-κB in primary AML cells and speculate that this activity contributes to the efficacy of PTL. However, previous genetic studies using a dominant-negative repressor of NF-κB activity have shown that inhibition of NF-κB alone is not sufficient to mediate the robust cell death observed with PTL. Rather, blockade of the NF-κB pathway appears to sensitize primary AML cells to death and induces a relatively slow spontaneous apoptosis (~50% cell death in 36 h) (Guzman et al., 2002). Similarly, studies by Romano et al. (2000) showed that treatment of primary AML blasts with NF-κB decoy oligonucleotides was not sufficient to induce a strong apoptotic response.

Consequently, PTL must be affecting other pathways relevant to AML-specific survival. One such pathway appears to be mediated by the activity of p53. PTL induced rapid up-regulation of p53 protein with concomitant phosphorylation on serine (Woynarowski & Konopa, 1981).

Ovarian Carcinoma

Results suggest that parthenolide may induce apoptotic cell death in ovarian carcinoma cell lines by activating the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The apoptotic effect of parthenolide appears to be mediated by the formation of reactive oxygen species and the depletion of GSH. Parthenolide might be beneficial in the treatment of epithelial ovarian adenocarcinoma and combination therapy (Kwak et al., 2013).

Epithelial-to-Mesenchymal Transition (EMT)

Detyrosinated tubulin, a post-translational modification of α-tubulin and a hallmark of stable microtubules, has gained recent attention given its association with tumor progression, invasiveness, and chemoresistance. Also, epithelial-to-mesenchymal transition (EMT) promotes tubulin detyrosination through tubulin tyrosine ligase (TTL) suppression. Given the induction of EMT associated with inflammation and cancer progression, Whipple et al. (2013) tested anti-inflammatory nuclear factor-kappaB (NF-κB) inhibitors on a panel of human breast carcinoma cells to examine their effects on detyrosinated tubulin to identify more specific tubulin-directed anti-cancer treatments.

Breast Cancer

Sesquiterpene lactones, parthenolide and costunolide, selectively decrease detyrosinated tubulin independent of their inhibition of NF-κB. Live-cell scoring of suspended cells treated with parthenolide and costunolide show reduction in the frequency of microtentacles and inhibition of reattachment. Selective targeting of detyrosinated tubulin with parthenolide and costunolide can reduce McTN frequency and inhibit tumor cell reattachment. These actions are independent of their effects on NF-κB inhibition, presenting a novel anti-cancer property and therapeutic opportunity to selectively target a stable subset of microtubules in circulating tumor cells to reduce metastatic potential with less toxicity in breast cancer patients (Whipple et al., 2013).

References

Bork PM, Schmitz ML, Kuhnt M, Escher C, Heinrich M. (1997). Sesquiterpene lactone containing Mexican Indian medicinal plants and pure sesquiterpene lactones as potent inhibitors of transcription factor NF-kappaB. FEBS Lett, 402:85-90.


Gunn EJ, Williams JT, Huynh DT, et al. (2011). The natural products parthenolide and andrographolide exhibit anti-cancer stem cell activity in multiple myeloma. Leuk Lymphoma, 52(6):1085-97.


Guzman ML, Rossi RM, Karnischky L, et al. (2005). The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cell. Blood, 105(11): 4163–4169. doi: 10.1182/blood-2004-10-4135.


Guzman ML, Swiderski CF, Howard DS, et al. (2002). Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A, 99:16220-16225.


Koprowska K, Czyz M. (2010). Molecular mechanisms of parthenolide's action: Old drug with a new face. Postepy Hig Med Dosw, 64:100-14.


Kwak SW, Park ES, Lee CS. (2013). Parthenolide induces apoptosis by activating the mitochondrial and death receptor pathways and inhibits FAK-mediated cell invasion. Mol Cell Biochem.


Romano MF, Lamberti A, Bisogni R, et al. (2000). Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-kappa B/Rel-specific decoy oligodeoxynucleotides. Gene Ther, 7:1234-1237.


Whipple RA, Vitolo MI, Boggs AE, et al. (2013). Parthenolide and costunolide reduce microtentacles and tumor cell attachment by selectively targeting detyrosinated tubulin independent from NF- κ B inhibition. Breast Cancer Res,15(5):R83.


Woynarowski JM, Konopa J. (1981). Inhibition of DNA biosynthesis in HeLa cells by cytotoxic and anti-tumor sesquiterpene lactones. Mol Pharmacol,19:97-102.

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)

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.


Hou X, Yuan X, Zhang B, Wang S, Chen Q. (2013). Screening active anti-breast cancer compounds from Cortex Magnolia officinalis by 2D LC-MS. J Sep Sci, 36(4):706-12. doi: 10.1002/jssc.201200896.


Kong ZL, Tzeng SC, Liu YC. (2005). Cytotoxic neolignans: an SAR study. Bioorg Med Chem Lett, 15: 163–6.


Konoshima T, Kozuka M, Tokuda H, et al. (1991). Studies on inhibitors of skin tumor promotion. IX. Neolignans from Magnolia officinalis. J Nat Prod, 54: 816–22.


Liu Y, Chen L, He X, et al. (2010). Enhancement of therapeutic effectiveness by combining liposomal honokiol with cisplatin in ovarian carcinoma. International Journal of Gynecological Cancer, 18(4), 652-659.


Liu SH, Wang KB, Lan KH, et al. (2012). Calpain/SHP-1 interaction by honokiol dampening peritoneal dissemination of gastric cancer in nu/nu mice. PLoS One, 7(8):e43711.


Munroe ME, Arbiser JL, Bishop GA. (2007). Honokiol, a natural plant product, inhibits inflammatory signals and alleviates inflammatory arthritis. J. Immunol., 179(2):753–763


Nagalingam A, Arbiser JL, Bonner MY, Saxena NK, Sharma D. (2012). Honokiol activates AMP-activated protein kinase in breast cancer cells via an LKB1-dependent pathway and inhibits breast carcinogenesis. Breast Cancer Research, 14:R35 doi:10.1186/bcr3128


Nagase H, Ikeda K, Sakai Y. (2001). Inhibitory Effect of Magnolol and Honokiol from Magnolia obovata on Human Fibrosarcoma HT-1080 Invasiveness in vitro. Planta Med, 67(8): 705-708. DOI: 10.1055/s-2001-18345


Ponnurangam S, Mammen JM, Ramalingam S, et al. (2012). Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells. Molecular Cancer Therapeutics, 11(4), 963-972. doi: 10.1371/journal.pone.0043711.


Shigemura K, Arbiser JL, Sun SY, et al. (2007). Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells. Cancer, 109(7), 1279-1289.


Tian W, Deng Y, Li L, et al. (2013). Honokiol synergizes chemotherapy drugs in Multi-drug-resistant breast cancer cells via enhanced apoptosis and additional programmed necrotic death. International Journal of Oncology, 42(2), 721-732. doi: 10.3892/ijo.2012.1739.


Wang Y, Yang Z, Zhao X. (2010). Honokiol induces parapoptosis and apoptosis and exhibits schedule-dependent synergy in combination with imatinib in human leukemia cells. Toxicology Mechanisms and Methods, 20(5), 234-241. doi: 10.3109/15376511003758831.


Wang T, Chen F, Chen Z, et al. (2004). Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J Gastroenterol, 10: 2205–8.


Wen J, Fu AF, Chen LJ, et al. (2009). Liposomal honokiol inhibits VEGF-D-induced lymphangiogenesis and metastasis in xenograft tumor model. International Journal of Cancer, 124(11), 2709-2718. doi: 10.1002/ijc.24244.


Xu D, Lu Q, Hu X. (2006). Down-regulation of P-glycoprotein expression in MDR breast cancer cell MCF-7/ADR by honokiol. Cancer Letters, 243(2), 274-280.


Yang SE, Hsieh MT, Tsai TH, Hsu SL. (2002). Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells. Biochemical Pharmacology, 63(9), 1641-1651.

Source

Eliaz I. (2013). Honokiol research review: A promising extract with multiple applications. Natural Medicine Journal., 5(7). Retrieved from http://www.naturalmedicinejournal.com/article_content.asp?edition=1.

5-LOX, ABC, ABCG2, Akt, angiogenesis, anti-apoptotic, Anti-cancer, anti-inflammatory, anti-oxidant, anti-proliferative, AP-1, apoptosis, apoptosis-inducing, Apoptotic, attenuation of immune suppression, Bcl-2, Breast cancer, cancer stem cells, Chapter 7 Isolates and Cancer Research, chemo-preventive, chemo-preventive activity, Chemoprevention, COC1/DDP, COX-2, Curcuma longa, CXCR-4, DR5, EGFR, Genitourinary cancers, HER-2, IL-1, IL-6, Immune, inflammation, KBV20C, Lung cancer, Lymphoma, MDR, Melanoma, metastasis, Neurological cancers, Neuropathy, Notch, Ovarian cancer, p53, Pancreatic cancer, PI3K, PI3K/Akt, Prostate cancer, Sarcoma, SGC7901/VCR, Squamous cell carcinoma, STAT, TNF, TRAIL, tumor-inhibitory, VEGF, VEGF

Curcumin

Cancer: Colorectal., prostate, pancreatic

Action: MDR, chemo-preventive activity, anti-inflammatory, attenuation of immune suppression

Chemo-preventive Activity

Curcumin is a naturally occurring, dietary polyphenolic phytochemical that is under preclinical trial evaluation for cancer-preventive drug development. It is derived from the rhizome of Curcuma longa L. and has both anti-oxidant and anti-inflammatory properties; it inhibits chemically-induced carcinogenesis in the skin, forestomach, and colon when it is administered during initiation and/or postinitiation stages. Chemo-preventive activity of curcumin is observed when it is administered prior to, during, and after carcinogen treatment as well as when it is given only during the promotion/progression phase (starting late in premalignant stage) of colon carcinogenesis (Kawamori et al., 1999)

Anti-inflammatory

With respect to inflammation, in vitro, it inhibits the activation of free radical-activated transcription factors, such as nuclear factor κB (NFκB) and AP-1, and reduces the production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-8 (Chan et al., 1998)

Prostate Cancer

In addition, NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin may abrogate their survival mechanisms (Mukhopadhyay et al., 2001).

Pancreatic Cancer

In patients suffering from pancreatic cancer, orally-administered curcumin was found to be well-tolerated and despite limited absorption, had a reasonable impact on biological activity in some patients. This was attributed to its potent nuclear factor-kappaB (NF-kappaB) and tumor-inhibitory properties, against advanced pancreatic cancer (Dhillon et al., 2008)

MDR

Curcumin, the major component in Curcuma longa (Jianghuang), inhibited the transport activity of all three major ABC transporters, i.e. Pgp, MRP1 and ABCG2 (Ganta et al., 2009).

Curcumin reversed MDR of doxorubicin or daunorubicin in K562/DOX cell line and decreased Pgp expression in a time-dependent manner (Chang et al., 2006). Curcumin enhanced the sensitivity to vincristine by the inhibition of Pgp in SGC7901/VCR cell line (Tang et al., 2005). Moreover, curcumin was useful in reversing MDR associated with a decrease in bcl-2 and survivin expression but an increase in caspase-3 expression in COC1/DDP cell line (Ying et al., 2007).

The cytotoxicity of vincristine and paclitaxel were also partially restored by curcumin in resistant KBV20C cell line. Curcumin derivatives reversed MDR by inhibiting Pgp efflux (Um et al., 2008). A chlorine substituent at the meta-or para-position on benzamide improved MDR reversal [72]. Bisdemethoxycurcumin modified from curcumin resulted in greater inhibition of Pgp expression (Limtrakul et al., 2004).

Attenuation of Immune Suppression

Curcumin (a chalcone) exhibited toxicity to human neural stem cells (hNSCs). Although oridonin (a diterpene) showed a null toxicity toward hNSCs, it repressed the enzymatic function only marginally in contrast to its potent cytotoxicity in various cancer cell lines. While the mode of action of the enzyme-polyphenol complex awaits to be investigated, the sensitivity of enzyme inhibition was compared to the anti-proliferative activities toward three cancer cell lines.

The IC50s obtained from both sets of the experiments indicate that they are in the vicinity of micromolar concentration with the enzyme inhibition slightly more active.

These results suggest that attenuation of immune suppression via inhibition of IDO-1 enzyme activity may be one of the important mechanisms of polyphenols in chemoprevention or combinatorial cancer therapy (Chen et al., 2012).

Cancer Stem Cells

In cancers that appear to follow the stem cell model, pathways such as Wnt, Notch and Hedgehog may be targeted with natural compounds such as curcumin or drugs to reduce the risk of initiation of new tumors. Disease progression of established tumors could also potentially be inhibited by targeting the tumorigenic stem cells alone, rather than aiming to reduce overall tumor size.

Cancer treatments could be evaluated by assessing stem cell markers before and after treatment. Targeted stem cell specific treatment of cancers may not result in 'complete' or 'partial' responses radiologically, as stem cell targeting may not reduce the tumor bulk, but eliminate further tumorigenic potential. These changes are discussed using breast, pancreatic, and lung cancer as examples (Reddy et al., 2011).

Multiple Cancer Effects; Cell-signaling

Curcumin has been shown to interfere with multiple cell signaling pathways, including cell-cycle (cyclin D1 and cyclin E), apoptosis (activation of caspases and down-regulation of anti-apoptotic gene products), proliferation (HER-2, EGFR, and AP-1), survival (PI3K/AKT pathway), invasion (MMP-9 and adhesion molecules), angiogenesis (VEGF), metastasis (CXCR-4) and inflammation (NF- κB, TNF, IL-6, IL-1, COX-2, and 5-LOX).

The activity of curcumin reported against leukemia and lymphoma, gastrointestinal cancers, genitourinary cancers, breast cancer, ovarian cancer, head and neck squamous cell carcinoma, lung cancer, melanoma, neurological cancers, and sarcoma reflects its ability to affect multiple targets (Anand et al., 2008).

Anti-inflammatory; Cell-signaling

Curcumin, a liposoluble polyphenolic pigment isolated from the rhizomes of Curcuma longa L. (Zingiberaceae), is another potential candidate for new anti-cancer drug development. Curcumin has been reported to influence many cell-signaling pathways involved in tumor initiation and proliferation. Curcumin inhibits COX-2 activity, cyclin D1 and MMPs overexpresion, NF-kB, STAT and TNF-alpha signaling pathways and regulates the expression of p53 tumor suppressing gene.

Curcumin is well-tolerated but has a reduced systemic bioavailability. Polycurcumins (PCurc 8) and curcumin encapsulated in biodegradable polymeric nanoparticles showed higher bioavailability than curcumin together with a significant tumor growth inhibition in both in vitro and in vivo studies (Cretu et al., 2012). Curcumin also sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5) (Jung et al., 2005).

Curcumin and bioavailability

Curcumin, a major constituent of the spice turmeric, suppresses expression of the enzyme cyclooxygenase 2 (Cox-2) and has cancer chemo-preventive properties in rodents. It possesses poor systemic availability. Marczylo et al. (2007) explored whether formulation with phosphatidylcholine increases the oral bioavailability or affects the metabolite profile of curcumin. Their results suggest that curcumin formulated with phosphatidylcholine furnishes higher systemic levels of parent agent than unformulated curcumin.

Curcuminoids are poorly water-soluble compounds and to overcome some of the drawbacks of curcuminoids, Aditya et al. (2012) explored the potential of liposomes for the intravenous delivery of curcuminoids. The curcuminoids-loaded liposomes were formulated from phosphatidylcholine (soy PC). Curcumin/curcuminoids were encapsulated in phosphatidylcholine vesicles with high yields. Vesicles in the size range around 200 nm were selected for stability and cell experiments. Liposomal curcumin were found to be twofold to sixfold more potent than corresponding curcuminoids. Moreover, the mixture of curcuminoids was found to be more potent than pure curcumin in regard to the anti-oxidant and anti-inflammatory activities (Basnet et al., 2012). Results suggest that the curcumin-phosphatidylcholine complex improves the survival rate by increasing the anti-oxidant activity (Inokuma et al., 2012). Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases (Wang et al., 2012). Data demonstrate that treatment with curcumin dissolved in sesame oil or phosphatidylcholine curcumin improves the peripheral neuropathy of R98C mice by alleviating endoplasmic reticulum stress, by reducing the activation of unfolded protein response (Patzk- et al., 2012).

References

Aditya NP, Chimote G, Gunalan K, et al. (2012). Curcuminoids-loaded liposomes in combination with arteether protects against Plasmodium berghei infection in mice. Exp Parasitol, 131(3):292-9. doi: 10.1016/j.exppara.2012.04.010.


Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB. (2008). Curcumin and cancer: An 'old-age' disease with an 'age-old' solution. Cancer Letters, 267(1):133–164. doi: 10.1016/j.canlet.2008.03.025.


Basnet P, Hussain H, Tho I, Skalko-Basnet N. (2012). Liposomal delivery system enhances anti-inflammatory properties of curcumin. J Pharm Sci, 101(2):598-609. doi: 10.1002/jps.22785.


Chan MY, Huang HI, Fenton MR, Fong D. (1998). In Vivo Inhibition of Nitric Oxide Synthase Gene Expression by Curcumin, a Cancer-preventive Natural Product with Anti-Inflammatory Properties. Biochemical Pharmacology, 55(12), 1955-1962.


Chang HY, Pan KL, Ma FC, et al. (2006). The study on reversing mechanism of Multi-drug resistance of K562/DOX cell line by curcumin and erythromycin. Chin J Hem, 27(4):254-258.


Chen SS, Corteling R, Stevanato L, Sinden J. (2012). Polyphenols Inhibit Indoleamine 3,5-Dioxygenase-1 Enzymatic Activity — A Role of Immunomodulation in Chemoprevention. Discovery Medicine.


Cre ţ u E, Trifan A, Vasincu A, Miron A. (2012). Plant-derived anti-cancer agents – curcumin in cancer prevention and treatment. Rev Med Chir Soc Med Nat Iasi, 116(4):1223-9.


Dhillon N, Aggarwal BB, Newman RA, et al. (2008). Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res,14(14):4491-9. doi: 10.1158/1078-0432.CCR-08-0024.


Ganta S, Amiji M. (2009). Coadministration of paclitaxel and curcumin in nanoemulsion formulations To overcome Multi-drug resistance in tumor cells. Mol Pharm, 6(3):928-939. doi: 10.1021/mp800240j.


Inokuma T, Yamanouchi K, Tomonaga T, et al. (2012). Curcumin improves the survival rate after a massive hepatectomy in rats. Hepatogastroenterology, 59(119):2243-7. doi: 10.5754/hge10650.


Jung EM, Lim JH, Lee TJ, et al. (2005). Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated up-regulation of death receptor 5 (DR5). Carcinogenesis, 26(11):1905-1913.


Kawamori T, Lubet R, Steele V E, et al. (1999). Chemo-preventive Effect of Curcumin, a Naturally Occurring Anti-Inflammatory Agent, during the Promotion/Progression Stages of Colon Cancer. Cancer Research, 59(3), 597-601.


Limtrakul P, Anuchapreeda S, Buddhasukh D. (2004). Modulation of human Multi-drug resistance MDR-1 gene by natural curcuminoids. BMC Cancer, 4:13.


Marczylo TH, Verschoyle RD, Cooke DN, et al. (2007). Comparison of systemic availability of curcumin with that of curcumin formulated with phosphatidylcholine. Cancer Chemother Pharmacol, 60(2):171-7.


Mukhopadhyay A, Bueso-Ramos C, Chatterjee D, Pantazis P, & Aggarwal., B. B. (2001). Curcumin downregulates cell survival mechanisms in human prostate cancer cell lines. Oncogene, 20(52), 7597-7609.


Patzk- A, Bai Y, Saporta MA, et al. (2012). Curcumin derivatives promote Schwann cell differentiation and improve neuropathy in R98C CMT1B mice. Brain, 135(Pt 12):3551-66. doi: 10.1093/brain/aws299.


Reddy RM, Kakarala M, Wicha MS. (2011). Clinical trial design for testing the stem cell model for the prevention and treatment of cancer. Cancers (Basel), 3(2):2696-708. doi: 10.3390/cancers3022696.


Tang XQ, Bi H, Feng JQ, Cao JG. (2005). Effect of curcumin on Multi-drug resistance in resistant human gastric carcinoma cell line SGC7901/VCR. Acta Pharmacol Sin, 26(8):1009-1016.


Um Y, Cho S, Woo HB, et al. (2008). Synthesis of curcumin mimics with Multi-drug resistance reversal activities. Bioorg Med Chem,16(7):3608-3615.


Wang LL, Sun Y, Huang K, Zheng L. (2012). Curcumin, a potential therapeutic candidate for retinal diseases. Mol Nutr Food Res, 57(9):1557-68. doi: 10.1002/mnfr.201200718.


Ying HC, Zhang SL, Lv J. (2007). Drug-resistant reversing effect of curcumin on COC1/DDP and its mechanism. J Mod Oncol, 15(5):604-607.

angiogenesis, Anti-angiogenic, Anti-cancer, apoptosis, Apoptotic, BAX, Bcl-2, CD31, CDK4, Chapter 7 Isolates and Cancer Research, PCNA, Pro-apoptotic, promotes apoptosis, Rectal cancer, STAT, STAT3, VEGF, VEGF, VEGFR, VEGFR-2

Spica Prunellae Extract

Cancer: Colorectal

Action: Promotes apoptosis, anti-angiogenic, induces angiogenesis

Constitutive activation of STAT3 is one of the major oncogenic pathways involved in the development of various types of malignancies including colorectal cancer (CRC); and thus becomes a promising therapeutic target. Spica Prunellae has long been used as an important component in many traditional Chinese medicine formulas to clinically treat CRC. Previously, Lin et al., (2013) found that Spica Prunellae inhibits CRC cell growth through mitochondrion-mediated apoptosis. Furthermore, we demonstrated its anti-angiogenic activities in vivo and in vitro.

CRC mouse xenograft model was generated by subcutaneous injection of human colon carcinoma HT-29 cells into nude mice. Animals were given intra-gastric administration with 6 g/kg of the ethanol extract of Spica Prunellae (EESP) daily, 5 days a week for 16 days. Body weight and tumor growth were measured every two days. Tumor growth in vivo was determined by measuring the tumor volume and weight. HT-29 cell viability was examined by MTT assay. Cell apoptosis and proliferation in tumors from CRC xenograft mice was evaluated via immunohistochemical staining (IHS) for TUNEL and PCNA, and the intratumoral microvessel density (MVD) was examined by using IHS for the endothelial cell-specific marker CD31. The activation of STAT3 was evaluated by determining its phosphorylation level using IHS. The mRNA and protein expression of Bcl-2, Bax, Cyclin D1, VEGF-A and VEGFR2 was measured by RT-PCR and IHS, respectively.

EESP treatment reduced tumor volume and tumor weight but had no effect on body weight change in CRC mice; decreasedanti-angiogenic cell viability in a dose-dependent manner, suggesting that EESP displays therapeutic efficacy against colon cancer growth in vivo and in vitro, without apparent toxicity. In addition, EESP significantly inhibited the phosphorylation of STAT3 in tumor tissues, indicating its suppressive action on the activation of STAT3 signaling. Consequently, the inhibitory effect of EESP on STAT3 activation resulted in an increase in the pro-apoptotic Bax/Bcl-2 ratio, decrease in the expression of the pro-proliferative Cyclin D1 and CDK4, as well as down-regulation of pro-angiogenic VEGF-A and VEGFR-2 expression. Finally, these molecular effects led to the induction of apoptosis, the inhibition of cell proliferation and tumor angiogenesis.

Spica Prunellae possesses a broad range of anti-cancer activities due to its ability to affect STAT3 pathway, suggesting that Spica Prunellae could be a novel potent therapeutic agent for the treatment of CRC.

Reference

Lin W, Zheng L, Zhuang Q, Zhao J, et al. (2013) Spica prunellae promotes cancer cell apoptosis, inhibits cell proliferation and tumor angiogenesis in a mouse model of colorectal cancer via suppression of stat3 pathway. BMC Complement Altern Med. 2013 Jun 24;13(1):144.