Cannabidiol-Induced Apoptosis in Human Leukemia Cells

http://molpharm.aspetjournals.org/content/70/3/897.full

Cannabidiol-Induced Apoptosis in Human Leukemia Cells: A Novel Role of Cannabidiol in the Regulation of p22^phox and Nox4 Expression

1. Robert J. McKallip,
2. Wentao Jia,
3. Jerome Schlomer,
4. James W. Warren,
5. Prakash S. Nagarkatti and
6. Mitzi Nagarkatti

+ Author Affiliations

1. Department of Pathology, Microbiology, and Immunology, the University of South Carolina School of Medicine, Columbia, South Carolina (R.J.M., J.W.W., P.S.N., M.N.); and Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia (W.J., J.S.)

1. Address correspondence to:
   Dr. Robert J. McKallip. Department of Pathology, Microbiology and Immunology. University of South Carolina School of Medicine, 6439 Garner's Ferry Road, Columbia, SC 29209. E-mail: rmckallip@gw.med.sc.edu

 

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Abstract

In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c. It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22^phox. Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS) levels could be blocked by treatment with the ROS scavengers or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22^phox expression, may be a novel and highly selective treatment for leukemia.

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Marijuana has been suggested as a potent therapeutic agent alleviating such complications as intraocular pressure in glaucoma and cachexia, nausea, and pain in AIDS and cancer patients. A number of recent studies now suggest the possible use of these compounds for the treatment of cannabinoid receptor-expressing tumors. For example, anandamide was shown to inhibit the proliferation of the human breast cancer cell lines MCF-7 and EFM-19 in vitro (De Petrocellis et al., 1998). In addition, THC was shown to induce apoptosis in human prostate PC-3 cells and in C6 glioma cells in culture (Sanchez et al., 1998; Ruiz et al., 1999; Galve-Roperh et al., 2000). THC-induced apoptosis involved cannabinoid receptor-dependent (Sanchez et al., 1998; Galve-Roperh et al., 2000) or -independent pathways (Ruiz et al., 1999). Such studies have triggered interest in targeting cannabinoid receptors in vivo to induce apoptosis in transformed cells. To this end, cannabinoids were shown to inhibit the growth of C6 glioma cells in vivo (Sanchez et al., 2001). Furthermore, recent studies from our laboratory demonstrated that targeting cannabinoid receptors may be a novel approach to treating lymphoblastic disease (McKallip et al., 2002).

A significant limitation to the use of a number of these compounds is their unwanted psychotropic activity. Cannabidiol (CBD) is a nonpsychoactive derivative of marijuana that is currently being examined for its use in the treatment of cancer. For example, Massi et al. (2004) demonstrated that cannabidiol was capable of suppressing the proliferation of human glioma cell lines. In addition, the HL-60 myeloblastic cell line was shown to be sensitive to CBD-induced apoptosis, whereas monocytes from healthy subjects were relatively resistant to CBD-induced apoptosis, suggesting that CBD may be effective at treating acute myelogenous leukemia (Gallily et al., 2003).

Although a number of reports demonstrate the ability of CBD to induce apoptosis in tumor cells, little work has been done demonstrating CBD mechanism of action. Massi et al. (2004) found that apoptosis in human glioma cell lines after exposure to CBD was mediated through CB2 receptor and the generation of reactive oxygen species (ROS). The generation of ROS can play an important role in the induction of apoptosis in T cells undergoing either activation-induced cell death or activated T cell autonomous cell death (Hildeman et al., 2003). Furthermore, the regulation of ROS generation can be significantly affected by NAD(P)H oxidases (Suzuki et al., 1998; Lee et al., 2000). Numerous studies have been carried out examining the ability of compounds to induce apoptosis in tumor cells by increasing ROS production (Kang et al., 2004; Kim et al., 2004; Chang et al., 2005; Hu and Brindle, 2005; Lebedeva et al., 2005). However, little is known about the ability of cannabinoids or signaling through cannabinoid receptors to regulate the expression or activity of NAD(P)H oxidases and/or to control of ROS generation in leukemia. However in a recent study, the NAD(P)H oxidase Nox5, which plays a significant role in mediating Ca²⁺-dependent ROS generation, was shown to be expressed in lymph nodes and the spleen, suggesting a possible role of NAD(P)H oxidases in the regulation of ROS production in cells of the immune system (Banfi et al., 2001). 

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http://molpharm.aspetjournals.org/content/70/3/897.full 

My Life. My Medicine. - Luke's Story

Luke is an eighteen-year-old medical marijuana patient in California. He has been suffering from a rare genetic skin disorder his whole life that causes his skin can to blister and tear with just slight contact. He is required to have hand and throat surgery every few years in order to live more comfortably.

At age sixteen, Luke first tried medical marijuana to help aid his symptoms. These symptoms include pain, night terrors, loss of appetite, insomnia, and isolation. Since then, Luke has seen improvements in all areas.

Because of their higher potency, Luke has found that medical marijuana concentrates help him sleep better. He discovered the G-Pen personal vaporizer for it's ease of use compared to traditional methods of ingestion.

Luke has now taken his crusade for the legalization of medical marijuana to new heights as he visits with the WeedMaps team to get the message out. Please take a moment and listen to Luke tell you his story of bravery and achievement over all odds. His story will inspire you.

Radiation treatments create cancer cells 30 times more potent than regular cancer

Tony Isaacs
Infowars.com
March 20, 2012

In a groundbreaking new study just published in the peer reviewed journal Stem Cells, researchers at UCLA’s Jonsson Comprehensive Cancer Center Department of Oncology found that, despite killing half of all tumor cells per treatment, radiation treatments on breast cancer transforms other cancer cells into cancer stem cells which are vastly more treatment-resistant than normal cancer cells. The new study is yet another blow to the failed and favored mainstream treatment paradigm of trying to cut out, poison out or burn out cancer symptoms (tumors) instead of actually curing cancer.

Senior study author Dr. Frank Pajonk, associate professor of radiation oncology at the Jonsson Center, reported that induced breast cancer stem cells (iBCSC) “were generated by radiation-induced activation of the same cellular pathways used to reprogram normal cells into induced pluripotent stem cells (iPS) in regenerative medicine.” Pjonk, who is also a scientist with the Eli and Edythe Broad Center of Regenerative Medicine at UCLA, added “It was remarkable that these breast cancers used the same reprogramming pathways to fight back against the radiation treatment.”

In the new study, Pajonk and his team irradiated normal non-stem cell cancer cells and placed them into mice. Through a unique imaging system, the researchers observed the cells differentiate into iBCSC in response to radiation treatments. Pjonk reported that the newly generated cells were remarkably similar to non-irradiated breast cancer stem cells. The team of researchers also found that the radiation-induced stem cells had a more than 30-fold increased ability to form tumors compared with non-irradiated breast cancer cells.

Despite mounting evidence, mainstream medicine clings to surgery, chemo and radiation and ignores natural solutions

Despite all the billions of dollars spent on cancer, the 40 year “war on cancer” has been a losing one by any honest evaluation. One hundred years ago, anywhere from 1 in 50 to perhaps 1 in 100 people could be expected to develop cancer. Now it is estimated that 1 in every 2 men and 1 in every 3 women will be diagnosed with cancer in their lifetimes. Despite more people around the world developing cancer and dying from cancer every year, mainstream medicine continues to cling to failed treatments which more often than not fail to eliminate the cancer and help cancer spread and return more aggressively than ever. Notably, two of the three major mainstream cancer treatments – radiation and chemo – are themselves highly carcinogenic.

One might think that the new study provided ample reasons to rethink using radiation. However, the study authors looked at the results as an opportunity to continue and enhance the use of radiation by finding ways to control the cell differentiation. What the scientists failed to note is that natural alternatives have already been found which prevent the development of cancer stem cells.

As just one example, Natural News reported in May 2010 that a University of Michigan study had found a compound in broccoli and broccoli sprouts which had the ability to target cancer stem cells. See:

• 

http://www.naturalnews.com/028822_broccoli_breast_cancer.html

The researchers failed to note how cancer cells fought against unnatural treatments. They also failed to take into account the mounting evidence that the best way to beat cancer as well as avoid it is to build and enhance our natural first line of defense – our immune system.

The safest and most effective way to enhance the natural immune system and fight cancer in general is by working with nature. It is also by far the least expensive way, and therein likely lies the rub. You can’t patent and profit from nature like you can with mainstream drugs and treatments.

Note: Neither NaturalNews nor this author condone the inhumane use of animals in medical studies.

Other sources included:

www.cancer.ucla.edu/Index.aspx?page=644
www.sciencedaily.com/releases/2012/02/120213185115.htm
www.naturalnews.com/cancer_cells.html
www.naturalnews.com/stem_cells.html

This article was originally published on Natural News.

I Will Not Be Pinkwashed: Komen's Race Is For Money, Not Cure

http://www.alternet.org/story/154010/i_will_not_be_pinkwashed:_komen%27s_race_is_for_money,_not_cure__/

Outrageous salaries, drug company ties, and less than a dime of every dollar looks for a cure.

February 4, 2012 |

It’s October. And that means, it’s prime pink season. It’s national Breast Cancer Awareness Month, that magical time of year when shades of pale pink are plastered onto every product, every container, every conceivable gadget or gizmo the Susan G. Komen Foundation can get its hands on. That iconic symbol of overlapped ribbon is supposed to adorn every man, woman and child who ever had a mother, grandmother, sister, daughter, niece or aunt who faced the horrifying struggle of breast cancer.

But I am not buying it.

Susan G. Komen: For Cure of Con?

Susan G. Komen for the Cure is a multimillion-dollar company with assets totaling over $390 million. Only 20.9% of these funds were reportedly used in the 2009-2010 fiscal year for research “for the cure.” Where does the rest of the money go? Let’s have a look. Health screening is 13.0%. Treatment is 5.6%. Fundraising is 10.0%. The largest chunk of the pie is going toward “public health education,” 39.1%. More on that later, but for now I’d like to take a look at the millions, or 11.3%, spent on “administrative costs.”

Click on this link from Susan G. Komen’s Form 990 from 2008 showing the salaries of some of its highest-paid employees. All non-profits have to file these with the IRS. "Part VII, Section AAa" show what the numbers in the columns represent, but cut out the board members listed as having no salary -- er, “reportable” salary.

What do we see? Note the dates of employment for some of the lesser-paid employees. Gary Dicovitsky, VP Development, for example, was paid $95,291 (plus $2,746) only from 10/08 to 3/09. Gary must have gotten a promotion since then, though. Because while it still lists his position as VP Development from 10/08 – 3/09, his salary from 2009 was $417,109. Oh, plus $18,091 in change.

I don’t know about you, but I would never expect directors of a charitable “non-profit” organization to make more than most doctors, lawyers, or even politicians. Their CEO and president, Hala G. Moddelmog, made $531,924, plus $26,683 in change. That's more than President Obama makes.

Here's another screenshot from 2009 Form 990, straight from Komen.org. Yup, more of the same. Curiously, these were the only employees listed in this type of form, similar to the 2008 one. Other employees were not listed with their position title.

In all, about 11% of Susan G. Komen for the Cure’s annual revenue goes toward employee salaries. And that adds up to a lot of money. But what about the rest?

"Public Health Education"

We have all seen the rallies with pink hats, pink T-shirts, pink staging, pink everything. Is this really making a difference?

The area in which Komen spends the highest percentage of funds is in “public health education,” in other words, bringing awareness to the population of the disease itself and the importance of screening for early detection of breast cancer. While that may be considered a worthwhile goal to some, it’s important to realize that Komen stands to profit from spreading that message.

It admits to about 10% of funds used for “fundraising,” but let’s be honest, the pink-ribbon-plastered “awareness” and”education” campaigns are often little more than a highly effective form of advertising — which in turn, brings in Komen’s millions. In other words, a way to raise funds for itself, while getting a pat on the back for its efforts to “save lives.”

One thing that doesn’t quite compute with me is how Komen’s mission of finding a “cure” — after all, that is its name — is congruent with putting over half its money toward promoting awareness and screening, for early detection of breast cancer. It’s not curing breast cancer to be aware that you could get it, nor is finding out that you have cancer and treating it in the early stages in hopes of entering into remission. That’s not a cure. Yet that is Komen’s largest promoted focus.

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Hemp Oil Hope forums up!

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BREAKING NEWS: Cannabis Science, Inc: Cannabis Oil Shrinks “One Of The Worst” Cancers

http://cannabiscureuk.wordpress.com/2012/01/11/breaking-news-cannabis-science-inc-cannabis-oil-shrinks-one-of-the-worst-cancers/

January 11, 2012

tags: cancer, cannabis, cannabis science, cannabis science inc., colorado, cure, death, heal, kill, mearijuana, medical, medicine

COLORADO’S pioneering biotech company Cannabis Science, Inc have released graphic photos of a patient, suffering with what their physician described as “the worst case of squamous cell carcinoma cancer” he had ever seen, being healed by cannabis oil administered at home.

From Skin Cancer.org “Squamous cell carcinoma (SCC) are the second most common form of skin cancer and are very small usually when they are first noticed. It is an uncontrolled growth of abnormal cells arising in the squamous cells, which compose most of the skin’s upper layers (the epidermis). SCCs often look like scaly red patches, open sores, or warts; they may crust or bleed. SCC is mainly caused by cumulative UV exposure over the course of a lifetime. It can become disfiguring and sometimes deadly if allowed to grow. An estimated 700,000 cases of SCC are diagnosed each year in the US, resulting in approximately 2,500 deaths.”

Cannabis After Radiot-Therapy Session

The first pictures released by Cannabis Science, Inc. show a tumour protruding the skull with two sinus-like holes in the top. Cannabis extract was then applied in and around the holes and to all of the surrounding tissue on the scalp whilst the patient was undergoing radiotherapy treatment which can be seen in the second photos. This kind of extract which contains cannabinoids such as THC and CBD is more commonly referred to as “hash oil” or “concentrate” in the fledging regulated cannabis industry in Colorado, most particularly, Denver. Colorado made it legal for patients with qualifying conditions, after citizens used ballot initiatives and petitions, to use Cannabis to treat their symptoms. MS, chronic pain and nausea are all qualifying conditions, not just life threatening ones.

Claims of cannabis’ ability to shrink tumours have been made for many years, but within the last decade the anecdotal evidence has stacked up to the point that pharmaceutical companies have started taking these claims more seriously. GW Pharmaceuticals, who are set to go global in 2012 with their cannabis tincture spray Sativex, are currently Phase III trialling their oromucosal mouth spray for cancer pain in both the UK and the US. It is already prescribed to a select number of MS suffers in parts of the UK and in continental Europe in countries such as Italy, Germany, Sweden and even Czech Republic this year.

What is visible in the next set of photos is what has been described as the cannabis oil being drawn out of the wound and, in the words of Cannabis Science, Inc., “killing the cancer cells from these lesions”. If this is “killing” the cancer cells then surely this must be an indication that the anecdotal claims and evidence that we have seen more of in the press so recently and many times in 2011, shows that cannabis does cure cancer.

Cannabis oil killing cancer

Back in 1974, researchers at the Medical College of Virginia in Richmond inadvertently found the THC slowed the growth of cancer cells in mice with cancer of the lung, breast and a virus-induced leukemia. Their funding ended since the original goal was to determine its harmful effects to the immune system. In 2000 Guzman and his research team in Madrid, Spain demonstrated that injected THC could shrink or destroy brain cell tumors (Glioma) in rats. The 1974 studies were never published and in recent years there has been little coverage in the U.S. about Guzman’s work.

In 2006 a Canadian man by the name of Rick Simpson dropped the film Run From The Cure on the cannabis world with claims and a full video guide of how to make a cure for cancer from whole plant cannabis extract. Since then he has become a modern icon for the movement and his video has been used to help reach hundreds of thousands, if not millions, who need help to treat not only cancer but diseases affecting every part of the human system. He is now on the run as a fugitive from the DEA of America.

In 2011 the Daily Mail published the story of the two year old boy whose father secretly fed him cannabis oil through his feeding tube whist undergoing several treatments that were quickly killing him before the intervention of easily applicable cannabis oil. Also in a Medical Marijuana state. Why are the UK so behind this?

In the United Kingdom Her Majesty’s Government insist on the truth of their statement “cannabis has no medicinal benefits”, and occasionally add “in herbal form” to account for the fact that they allow GW Pharmaceuticals to grow 300 tonnes of the plant a year for… medical purposes. But that’s OK, they are licensed to extract oil from it to make Sativex, which is due to embark on a new cancer pain market worth £millions this year. Because the product Sativex contains CBD, or cannabidiol, which can moderate the effects of THC’s euphoric or ‘high’ effect, but also prolong it as it slows down its break down in the body, meaning it can be used more effectively over a longer period of time. This is what we call an FAAH inhibitor. (Just a little bit of cannabis science for you!)

U.S. Government Licenses Patent for Medical Marijuana

http://www.expertclick.com/NewsReleaseWire/US_Government_Licenses_Patent_for_Medical_Marijuana,201138687.aspx

U.S. Department of Health and Human Services is About to Award

Exclusive Rights to Apply Marijuana as a Medical Therapeutic

Deadline for Comment: Monday, Dec. 19

LOS ANGELES, CA – Dec. 15, 2011--The Union of Medical Marijuana Patients has just discovered that the U.S. Department of Health and Human Services is about to award an exclusive license to KannaLife Sciences, Inc. of New York to develop medical therapeutics based on the chemistry of cannabis. According to the notice in the Federal Register, public comments will be accepted through Monday, December 19.

"We find it hypocritical and incredible that on the one hand, the U.S. Department of Justice is persecuting medical cannabis patient associations, asserting that the federal government regards marijuana as having absolutely no medical value, despite overwhelming clinical evidence," said Union director James Shaw. "On the other hand, the Department of Health and Human Services is planning to grant patent rights with possible worldwide application to develop medicines based on cannabis."

While the Union applauds the U.S. government's efforts into researching the medical value of cannabis, Shaw said, "they should have affirmatively rescheduled cannabis when they discovered it had medical efficacy and, of course, it makes no sense for the government to provide U.S. Patent 6,630,507, which the government owns, to a single company with exclusive rights." He urged medical cannabis patient associations and patients using marijuana for medical reasons to protest this giveaway to one pharmaceutical firm.

Comments need to be submitted in writing by next Monday to Betty B. Tong, Ph.D., Senior Licensing and Patenting Manager, Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville MD 20852-3804, fax (301) 402-0220, or tongb@mail.nih.gov.

More information on this issue can be found at www.Unionmmp.org.

Scott Smith

The Union of Medical Marijuana Patients

Los Angeles, CA

310-254-4051

Jump To The Union of Medical Marijuana Patients