Noscapine near perfect?

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.