(no toxicity, w/doxorubucin in triple neg, crosses into brain)
NOSCAPINE
A SAFE COUGH SUPPRESSANT WITH NEWLY DISCOVERED EFFECTS IN TREATING CANCER AND STROKE
http://www.pcref.org/MedInsight%20-%...e%20Review.pdf
PATENT and description: http://www.freepatentsonline.com/6673814.html
More info:
http://www.noscapine.org/
Noscapine near perfect?
http://cancerx.wordpress.com/2009/05...-near-perfect/
May 11, 2009
Solid science, potential efficacy, minimal toxicity and low cost – that would be a nearly perfect anti-cancer, wouldn’t it?
This is not an entirely new one. Noscapine (also, see
NCI drug dictionary) a
naturally derived and existing ingredient of OTC cough medicines in some countries, it has more data backing its usefulness against cancer than its relative Naltrexone (a fellow off-label anti-cancer candidate which is opiate derived) and
works like the chemo drug paclitaxel (Taxol) but without many of the nasty side-effects, all of which has been known for some time.
So, what is Noscapine? It is a
non-opiate alkaloid from plants of the poppy family that makes up 1-10% of opium’s alkaloid content, but without significant pain killing properties. This agent is primarily used for its
antitussive (cough-suppressing) effects, and is approved for use as such in some countries, but not in the US.
Mechanism of Action
A review by Ye et al. from Emory, where much subsequent in vitro and in vivo research on its anti-cancer effects were done, presented as early as 1998 (Proc Natl Acad Sci, 17;95(4):1601-6.) demonstrated elegantly how Noscapine may inhibit cancer by interfering with microtubular function at the cellular level, thereby arresting cell growth and inducing cellular suicide or apoptosis, much like taxanes and the vinca alkaloids do.
Noscapine binds to tubulin and alters its conformation, resulting in a disruption of the dynamics of microtubule assembly (by increasing the time that microtubules spend idle in a paused state) unlike other tubulin inhibitors such as the taxanes and vinca alkaloids which affect microtubule polymerization. Perhaps more importantly,
Noscapine was able to inhibit cancer at doses which produced little or no toxicity, including no adverse effects on the primary immune response (Ke Y et al. Cancer Immunol Immunother. 2000 Jul;49(4-5):217-25). More recently, Newcomb et al. from New York also demonstrated
potential anti-angiogenic activity of Noscapine as an alternate anti-cancer mechanism (Int J Oncol. 2006 May;28(5):1121-30)
In Vitro
Noscapine inhibits paclitaxel resistant ovarian cancer cells (Zhou, J et al. J Biol Chem. 2002 Oct 18;277(42):39777-85); C6 rat glioma when administered alone, (as well as
augmented the cytotoxicity of radiation and chemotherapy upon C6 rat glioma cells when administered concomitantly – Surg Neurol. 2006 May;65(5):478-84), HL60 and K562 myelogenous leukemic cells Anticancer Drugs. 2007 Nov;18(10):1139-47),
In Vivo
Noscapine inhibits murine lymphoid tumors, human breast and bladder in nude mice murine (Ye, 1998), prolonged survival in melanoma (Landen et al. Cancer Res. 2002 Jul 15;62(14):4109-14),
crosses the blood brain barrier and inhibited implanted C6 glioma in the rat model (Landen, Clin Cancer Res. 2004 Aug 1;10(15):5187-201), and has potent anti-cancer activity in the non-small cell lung cancer model Cancer Chemother Pharmacol. 2008 Dec;63(1):117-26).
Generating the most buzz was the last year’s demonstration by Dr. Barken of San Diego of Noscapine’s ability to inhibit progression and metastates (60% and 65% respectively) inPC3 human prostate cancer-bearing immunodeficient mice Anticancer Res. 2008 Nov-Dec;28(6A):3701-4.)
Clinical (human) Studies
Unfortunately, although a phase I/II
clinical trial of Noscapine (CB3304) for patients with refractory non-Hodgkin’s lymphoma and chronic lymphocytic leukemia at USC / Norris Cancer Center was planned in 2003, it was terminated early because of apparent funding issues. However,
interim results in 2005 on 12 patients recruited thus far suggested that one out of ten patients evaluable did have a partial response, and two other patients demonstrated stable disease. The research team stated that they were encouraged by the results.
Cougar Biotech Inc. currently has a phase I
trial of noscapine in patients with multiple myeloma ongoing at the Center for Lymphoma and Myeloma/Weill Cornell Medical College and Columbia University Medical Center, and Dr. Barken of the Prostate Cancer Research and Educational Foundation (PC-REF) in San Diego, California, is planning on facilitating clinical trials with noscapine in prostate cancer.
My Take
Potentially useful against CLL leukemia/lymphoma/myeloma, prostate cancer, non-small cell lung cancer, glioma (administered alone or in combination with chemo and/or radiation to enhance cytotoxicity), hormone resistant breast cancer, or perhaps co-administered with taxanes.
Distinct advantages include i) oral bioavailability, ii) encouraging experimental data, iii) low toxicity, iv) low cost, and v) synergistic potential with other modalities and drugs.
The future lies with more affirmative clinical trials and the development of
more potent derivatives such as 9-bromonoscapine (Mol Cancer Ther. 2006 Sep;5(9):2366-77) and to develop other analogs of Noscapine with higher tubulin binding activity and/or affect tubulin polymerization differently, or able to arrest cell cycle progression at lower concentrations.
A website dedicated to Noscapine for prostate cancer:
http://www.noscapine.org/
Mol Cancer Ther. 2006 Sep;5(9):2366-77.
Treatment of hormone-refractory breast cancer: apoptosis and regression of human tumors implanted in mice.
FULL TEXT
http://mct.aacrjournals.org/content/5/9/2366.full
Aneja R,
Zhou J,
Zhou B,
Chandra R,
Joshi HC.
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
raneja@emory.edu
Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type.
We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to
a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.
PMID: 16985071 [PubMed - indexed for MEDLINE]
Summary from
full text:
Although microtubule agents such as the taxanes and Vincas have been effective against hormone-resistant disease, they eventually present resistance. This is primarily due to three major mechanisms that give rise to drug resistance to antimicrotubule agents (see for example, ref.
62).
Besides, the overexpression of efflux pumps, tubulin mutations also tend to account for resistance to antimicrotubule drug therapy (
37). In addition, tubulin is a multigene family, and taken together, α-tubulin and β-tubulin subunits are encoded by at least 12 different genes in humans. Different tumor types express these isotypes of tubulin to different extents. Microtubule drugs interact differently to different isotypes. Therefore, the isotypic composition of tubulin determines the therapeutic outcome of a particular tumor (
63–
65).
We believe that the invention of 9-Br-nos as a nontoxic anticancer agent, particularly for hormone-resistant breast tumors, is a major advancement. Furthermore, noscapinoids have been shown to be poor substrates for drug efflux pumps (66) and are active against taxol-resistant cells (
45).
We thus conclude that
9-Br-nos clearly inhibits the cellular proliferation of both hormone-insensitive and hormone-sensitive breast cancer cells. 9-Br-nos is also active against the Adriamycin- and tamoxifen-resistant breast cancer phenotypes. Furthermore, it significantly inhibits tumor growth in hormone-resistant human breast tumor xenografts by inducing extensive apoptosis and prolonging longevity. Although the founding compound, noscapine, is already in clinical trials, 9-Br-nos represents an additional edge over noscapine because of its higher potency, by at least an order of magnitude, without compromising the nontoxic profile of noscapine, including the unaltered immunosurveillance system. Therefore, our preclinical data qualifies 9-Br-noscapine to undergo clinical trials.
PLoS One. 2011 Mar 15;6(3):e17733.
Antitumor activity of Noscapine in combination with Doxorubicin in triple negative breast cancer.
Chougule MB,
Patel AR,
Jackson T,
Singh M.
FREE TEXT
Source
College of Pharmacy, University of Hawaii, Hilo, Hawaii, United States of America.
Abstract
BACKGROUND:
The aim of this study was to investigate the anticancer activity and mechanism of action of Noscapine alone and in combination with Doxorubicin against triple negative breast cancer (TNBC).
METHODS:
TNBC cells were pretreated with Noscapine or Doxorubicin or combination and combination index values were calculated using isobolographic method. Apoptosis was assessed by TUNEL staining. Female athymic Nu/nu mice were xenografted with MDA-MB-231 cells and the efficacy of Noscapine, Doxorubicin and combination was determined. Protein expression, immunohistochemical staining were evaluated in harvested tumor tissues.
RESULTS:
Noscapine inhibited growth of MDA-MB-231 and MDA-MB-468 cells with the IC(50) values of 36.16±3.76 and 42.7±4.3 µM respectively. The CI values (<0.59) were suggestive of strong synergistic interaction between Noscapine and Doxorubicin and combination treatment showed significant increase in apoptotic cells.
Noscapine showed dose dependent reduction in the tumor volumes at a dose of 150-550 mg/kg/day compared to controls. Noscapine (300 mg/kg), Doxorubicin (1.5 mg/kg) and combination treatment reduced tumor volume by 39.4±5.8, 34.2±5.7 and 82.9±4.5 percent respectively and showed decreased expression of NF-KB pathway proteins, VEGF, cell survival, and increased expression of apoptotic and growth inhibitory proteins compared to single-agent treatment and control groups.
CONCLUSIONS:
Noscapine potentiated the anticancer activity of Doxorubicin in a synergistic manner against TNBC tumors via inactivation of NF-KB and anti-angiogenic pathways while stimulating apoptosis. These
findings suggest potential benefit for use of oral Noscapine and Doxorubicin combination therapy for treatment of more aggressive TNBC.
- PMID:
- 21423660
- [PubMed - in process]
- PMCID: PMC3057970
http://www.cougarbiotechnology.com/cb3304.html
Noscapine (CB3304) is an orally active alkaloid derived from opium. Preclinical studies have shown that noscapine is a microtubule targeting agent that alters microtubule dynamics (see Figure 1 below), blocks mitosis, and causes apoptosis. Preclinical antitumor activity has been demonstrated in a number of tumor types including preclinical models of lymphoma, breast cancer, bladder cancer, melanoma and glioblastoma.
Noscapine has also shown the ability to inhibit the proliferation of both paclitaxel sensitive and paclitaxel resistant human ovarian carcinoma cell lines.
Figure 1: Gallery of video frames, 10 seconds apart, demonstrating the effect of CB3304 (noscapine) on microtubule dynamics (fixed pixel positions are marked with arrowheads). In control cells, microtubules alternated between phases of growth and shortening; therefore, the position of their plus ends changes significantly over time. In cells treated with CB3304, microtubule dynamics were suppressed; therefore, the position of their plus ends was unaltered. (Landen, Cancer Research, 2002)
A
Phase I/II trial of noscapine in patients with multiple myeloma is currently ongoing at the Center for Lymphoma and Myeloma/Weill Cornell Medical College and Columbia University Medical Center.
http://clinicaltrials.gov/ct2/show/NCT00912899
1: Recent Pat Antiinfect Drug Discov. 2009 Nov 1. [Epub ahead of print]Links
- Recent Patents Reveal Microtubules as Persistent Promising Target for Novel Drug Development for Cancers.
Bughani U, Li S, Joshi HC.
Department of Cell Biology, Emory University School of Medicine, Whitehead Medical Building, 615 Michael Street, Atlanta, GA 30322, USA. joshi@cellbio.emory.edu.
Conventionally, the successful targets for the drug development in cancer range from the DNA damage, replication, signal transduction pathways, hormones, cytokines, anti-angiogenic agents, and radio/photo-sensitizers. They dominate the therapeutic arena after the initial debulking surgery. More recently, tubulin, the primary constituent of microtubules (MTs), has made a fairly successful debut in the therapeutic armamentarium. Tubulin binding drugs come in two classes: that depolymerize microtubules and that over-polymerize and bundle them. Microtubule (MT) binding drugs are in some ways superior in nature primarily because of their less debilitating side effects when compared to the generalized DNA metabolism targeting agents, and many new promising patents are being funneled into the drug development pipeline. Nevertheless, many of these relatively new agents still face challenges relating to their delivery methods, bioavailability, toxicities, and the inevitable resistance shared by all chemotherapeutics. Finally, we disclose a new genre of anti-MT drugs, noscapinoids that have just begun climbing the clinical trials ladder. The lead compound, noscapine, is a plant derived, orally available, minimally-toxic (if at all) agent that has shown phenomenal promise in the preclinical experimentation and Phase-I clinical trial. A rational approach based upon the precise molecular model of the tubulin-noscapine complex is bound to inspire novel and better therapeutic analogs in future.
PMID: 19673697
- 1: Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):92-7.
- The anti-cancer activity of noscapine: a review.
Mahmoudian M, Rahimi-Moghaddam P.
Razi Institute for Drug Research, Department of Pharmacology, Iran University of Medical Sciences, Tehran, Iran. masmah99@iums.ac.ir
Noscapine is an isoqiunoline alkaloid found in opium latex. Unlike most other alkaloids obtained from opium latex, noscapine is not sedative and has been used as antitussive drug in various countries. Recently, it has been introduced as an anti-mitotic agent. This drug can be used orally. When the resistance to other anti-cancer drugs such as paclitaxel manifests, noscapine might be effective. Therefore, noscapine and its analogs have great potential as novel anti-cancer agents.
PMID: 19149691 [PubMed - indexed for MEDLINE
1: Anticancer Res. 2008 Nov-Dec;28(6A):3701-4.
Noscapine inhibits human prostate cancer progression and metastasis in a mouse model.
Barken I, Geller J, Rogosnitzky M.
Prostate Cancer Research and Education Foundation, 5520 Wellesley St., Suite 103 B, La Mesa, CA 91942-2015, USA. drbarken@pcref.org
BACKGROUND: Noscapine, a non-toxic alkaloid and common constituent of cough medicine, stabilises tubulin. It inhibits the growth of several human and murine neoplasms, with no significant toxicity. Its effect on prostate cancer has not been evaluated. MATERIALS AND METHODS: Noscapine was administered orally (300 mg/kg per day) for 56 days to PC3 human prostate cancer-bearing immunodeficient mice (n=10). Immunodeficient control mice (n=10) received only diluent in an identical regimen. RESULTS: Mean total tumour weight was 0.42 +/- 0.23 g and 0.97 +/- 0.31 g (p<0.001) in the noscapine-treated group and the control group, respectively, without evidence of toxicity. Metastases occurred less frequently in the treatment than the control group (30% vs. 90%; p<0.05). CONCLUSION: Oral administration of noscapine limited tumour growth and lymphatic metastasis of PC3 human prostate cancer in this mouse model, supporting its therapeutic potential as a nontoxic and easily administered treatment for metastatic cancer.
- 1: Tidsskr Nor Laegeforen. 2009 Mar 12;129(6):540. Links
- [Noscapine and warfarin--a potentially dangerous interaction]
- [Article in Norwegian]
- Myhr K.
PMID: 19282895 [PubMed - indexed for MEDLINE
Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1601-6.
Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells.
Ye K,
Ke Y,
Keshava N,
Shanks J,
Kapp JA,
Tekmal RR,
Petros J,
Joshi HC.
Graduate Program in Biochemistry and Molecular Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
An alkaloid from opium, noscapine, is used as an antitussive drug and has low toxicity in humans and mice. We show that noscapine binds stoichiometrically to tubulin, alters its conformation, affects microtubule assembly, and arrests mammalian cells in mitosis. Furthermore, noscapine causes apoptosis in many cell types and has potent antitumor activity against solid murine lymphoid tumors (even when the drug was administered orally) and against human breast and bladder tumors implanted in nude mice. Because noscapine is water-soluble and absorbed after oral administration, its chemotherapeutic potential in human cancer merits thorough evaluation.
PMID: 9465062 [PubMed - indexed for MEDLINE]
http://www.pnas.org/content/95/4/1601.full#sec-15
Quote:
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To test whether noscapine can inhibit growth of human breast and bladder cancer cells, we did the in vitro proliferation assays, the IC50 values for MCF-7 and Renal 1983 cell lines were 42.3 μM and 39.1 μM, respectively. To test whether noscapine can also inhibit growth of human tumors in vivo, we implanted 3 × 106 MCF-7 human breast cancer cells at two axillary sites in 12 female athymic nude mice. After establishment of tumors (10–15 mm3), six mice were given intraperitoneally 3 mg of noscapine [120 mg/kg (body weight)] per day for 3 weeks. As shown in Fig. 6 B, human breast tumors regressed by 80% at the end of a 3-week treatment. TUNEL assay of the treated tumor sections (Fig. 6 D) showed increased apoptotic activity when compared with control untreated tumors (Fig. 6 C). In addition, in a similar treatment regime, we also measured more than 60% reduction of a human transitional cell carcinoma implanted in athymic mice (data not shown). We conclude that noscapine may have activity against a wide variety of human tumors.
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