May 17, 2010 by

Identification of Peptides Which Show Potential To Generate Cancer Stem Cell Specific Immune Responses

The use of the immune system to target cancer has been a therapeutic goal for over a century. The advantage of immunotherapy is the possibility of targeting cancer throughout the body in a non-toxic manner, thus allowing destruction of metastasis, and induction of immunological memory to protect from relapse. Unfortunately with exception of the recent FDA approval of Dendreon’s prostate cancer vaccine on April 29th, 2010 all other cancer vaccine Phase III clinical trials have failed. The company ImmunoCellular Therapeutics believes that one of the reasons for poor efficacy of previous trials revolves around the fact that they were targeting the wrong
type of tumor cell.

It is known that tumors are comprised of rapidly multiplying cells and "sleeping" cells. The cells that are dormant appear to act as stem cells in that they are capable of starting a brand new tumor when transplanted to mice. To date, cancer vaccines have been designed to kill rapidly multiplying tumor cells but not the dormant stem cells. ImmunoCellular Therapeutics has been collaborating with the Torrey Pines Institute to identify molecules found on tumor stem cells that can be used to generate vaccines. Today the company announced some progress in its quest.

The company claims to have identified several peptides which can generate T-cells capable of killing cells that express the protein CD133. This protein according to the press release, is found in high abundance on cancer stem cells. What is interesting is that this protein is also found on healthy, non-cancerous, stem cells such as circulating endothelial progenitor cells. Therefore it will be interesting to see if the vaccines that are being developed will have adverse effects. Theoretically the cancer stem cells should be more difficult to target with a vaccine as compared to non-malignant stem cells due to the fact that cancer stem cells generally secrete immune suppressive factors that protect them from the body’s attack.

Torrey Pines Institute and Immunocellular Therapeutics have expanded their existing research agreement to conduct additional studies to support an Investigational New Drug Application (IND) filing. This is an application to the FDA to ask for permission to perform clinical trials in humans.

Additionally, the press release stated that ImmunoCellular Therapeutics and the Torrey Pines Institute will work on research programs with other proteins found on cancer stem cells such as Numb and Notch.

Dr. Manish Singh, President and Chief Executive Officer of ImmunoCellular Therapeutics stated "We are excited by the discoveries to date that could prove
efficacious in treating cancer," he continued, "We look forward to expanding our relationship with the Torrey Pines Institute."

Filed Under: News, Stem Cell Research Tagged With: , , , ,
May 17, 2010 by

Success Stems From Adult Cells

The use of adult stem cells for conditions besides bone marrow transplant is most prevalent in the area of heart failure. Since the original study of Strauer et al in 2001 in which a 46-year old patient was administered bone marrow stem cells after a heart attack and experienced a profound improvement in cardiac function, more than a thousand patients have received adult stem cells for cardiac-associated conditions.

Today the story of Eddie Floyd, a small business owner from Austin, Texas was highlighted in an article describing his presentation to the Texas Alliance for Life. Mr. Floyed suffered a heart attack three years ago. The heart attack caused profound damage so as to make him eligible to participate in a clinical trial being conducted at the Texas Heart Institute using his own bone marrow stem cells. The trial involves administration of the stem cells using a special catheter to the blood vessels supplying the heart muscle.

Three years later, Mr Floyd is happy with the results. He explains that he has been able to resume normal daily activities. "There really isn’t anything that I can’t do because of my heart, that I’m aware of. [But] there are a few things I can’t do because of my belly…,"

Since the stem cells are from the patient’s own body, there is no possibility of rejection. He stated "They did not cause any kind of rejection, so I didn’t have to have any rejection-preventive medicine or anything like that…They were just generic stem cells that became heart."

In his talk Mr. Floyd explained that despite all of the media publicity and controversy around embryonic stem cells, these cells produced no benefit to patients like himself. There was one clinical trial in embryonic stem cells that was approved, which was Geron’s spinal cord injury protocol. The approval, however, was retracted before any patients were treated.

In contrast, adult stem cells such as the ones derived from the bone marrow have been used successfully not only in the treatment of heart failure, but other diseases such as liver failure, type 2 diabetes, and prevention of amputation in patients having poor circulation in the legs.

Currently adult stem cells are in clinical trials in the US and Western Europe. The most advanced adult stem cell types are in Phase III of trials, meaning that
if successful they will be sold as a drug within the next 1-3 years. Because Phase III trials have a placebo control arm, some patients do not want the risk
of being in a placebo group and therefore choose to go to clinics outside the US that offer this treatment. Once such clinic, Cellmedicine, has published
results on patients, such as a recent heart failure patient who underwent a profound recovery in heart function after treatment. The patient is described
in the peer reviewed journal International Archives of Medicine which is freely accessible at
www.intarchmed.com/content/pdf/1755-7682-3-5.pdf.

Filed Under: Adult Stem Cells, Heart Disease, News, Stem Cell Research Tagged With: , , , ,
May 17, 2010 by

Stem Cells Restore Tissue Affected By Acute Lung Injury

Researchers from the University of California San Francisco
presented data today at the ATS 2010 International Conference in New Orleans
demonstrating activity of adult stem cells in treatment of acute lung injury.
This is a common condition in intensive care units that causes respiratory
failure and often leads to death. The cause of acute lung injury is usually
blood borne bacterial infections (sepsis), major trauma, aspiration, or direct
infection of the lung in situations like pneumonia or severe viral infections.
Acute lung injury has a 40% mortality rate and strikes an average of 200,000
patients in the US a year.

In order to study the effects of stem cells in this
condition, human lungs that were not suitable for transplantation were pumped
with blood outside of the body and administered endotoxin, a component from
bacterial walls that causes lung failure in patients with sepsis.

The researchers demonstrated that bone marrow derived
mesenchymal stem cells where capable of preserving lung function and inhibiting
the inflammation when administered to the human lung. Perhaps most important
was the finding that water did not leak into the lung, which is one of the major
causes of respiratory impairment.

"We found that intravenous infusion of clinical grade cryo-preserved
allogeneic hMSC were effective in restoring the capacity of the alveolar
epithelium to resolve pulmonary edema when given after the establishment of E.
coli endotoxin-induced acute lung injury in an ex vivo perfused human lung
preparation," explained Jae-Woo Lee, M.D., who led the study in the laboratory
of Michael A. Matthay, M.D. "In addition, we found that intravenous infusion of
hMSC preferentially homed to the injured areas of the lung, which means that the
cells find their way from the bloodstream to the sites in the lung of injury."

This findings are of particular interest because stem cells
are usually used in the treatment of chronic conditions in which the
administered cells are accelerating/augmenting healing processes that usually
take weeks if not months. In contrast, the therapeutic effects of stem cells in
the context of acute lung injury occur in a matter of hours.

Previously the same research group administered adult stem
cells into the bronchioles of the lung and demonstrate therapeutic effects. The
possibility of injecting stem cells intravenously would possess several
advantages in the treatment of patients that are critically ill, this is because
these patients are usually under mechanical ventilation and the bronchoscopy
procedure may lead to complications.

"These results suggest that the intravenous route would be
ideal for potential clinical trials of hMSC for severe acute lung injury, a
syndrome of acute respiratory failure in critically ill patients that is
associated with 40 percent mortality," said Dr. Lee.

He continued "These results extend our recent publication,
which demonstrated that hMSC may have therapeutic potential clinically in
patients with severe acute lung injury. We need to do more experiments with
testing the effect of hMSC against live bacterial induced lung injury in the
perfused human lung and now advance to doing Phase I and II safety and efficacy
studies in patients."

In
their previous publication the group demonstrated that mesenchymal stem cells
produce the protein keratinocyte growth factor (KGF)-1 which is responsible in
large part for maintaining integrity of the lung. Additionally, they
demonstrated that even administration of proteins made by the mesenchymal stem
cells, without mesenchymal stem cells being in the mix, would also elicit
therapeutic effects.

Filed Under: Kidney and Lung, News, Stem Cell Research Tagged With: , , , ,
May 17, 2010 by

Stem Cell Institute Panama Clinic Case Report of Successful Treatment of Heart Failure Patient Published

Adult stem cell therapy is currently in numerous clinical trials in the United States and Internationally. A sample of ongoing trials can be seen at
www.clinicaltrials.gov if you search for the words "stem cell". In clinical trials the objective is to determine safety (in Phase I), efficacy in an unblinded manner (Phase II) and efficacy in a blinded manner (Phase III). Numerous stem cell clinical trials are in Phase II, meaning that although safety has been established there is a question of efficacy. Patients with terminal
diseases sometimes make the informed decision not to wait until efficacy trials are completed and to go to stem cell clinics that offer similar procedures being
performed in clinical trials, but without the risk of offering the patient a placebo. The additional benefit to patients of making this choice is that they are offered treatment rapidly, whereas getting into a clinical trial could mean months on a waiting list.

The stem cell clinic Cellmedicine has been offering this choice to patients. Unlike other stem cell clinics, Cellmedicine has made it a priority to publish its protocols, scientific rationale, and outcomes in the peer reviewed literature. This means that all the scientists and doctors in the world can learn about the work being performed at Cellmedicine and offer comments/suggestions on it.

Today Cellmedicine announced publication of a paper in the peer reviewed journal, International Archives of Medicine, of a patient with terminal heart failure who underwent profound recovery after receiving adult stem cell therapy. The publication is freely available at

http://www.intarchmed.com/content/pdf/1755-7682-3-5.pdf.

The patient discussed in the report was administered adult stem cells in November 2007, when his heart had an ejection fraction of 25-30%. The ejection fraction is a quantitative measurement of the heart’s pumping activity. On June 2008, August, and Oct 2009, this marker of function increased to 40%. The patient reported a major improvement in quality of life. Additionally, proteins in the blood associated with heart failure were decreased.

Given that the report was based on only one patient, doctors at the clinic are excited but still caution in their statements.

"Stem cell therapy is a new science, and although the results discussed in the paper are promising, only the conduct of double-blinded, placebo controlled trials will allow definitive conclusions to be drawn," said Dr. Paz Rodriguez, Medical Director of the Cellmedicine Panama clinic and coauthor of the study.

In the publication, Cellmedicine provides detailed rationale for how the stem cell therapy may be affecting the process of heart failure. Data from other studies was described which states that stem cells can:

a) Directly differentiate into new heart cells

b) Stimulate the body’s ability to generate new heart muscle by activating dormant stem cells that already exist in the heart

c) Cause formation of new blood vessels that accelerate the healing process.

Heart failure is only one of the conditions that Cellmedicine treats.

"To date our group has published results on multiple sclerosis, non-ischemic heart failure, and Duchenne Muscular Dystrophy patients in collaboration with major
American Universities including University of California San Diego, Indiana University, and University of Utah. By publishing our data in a scientific forum, we welcome discussion and interaction, which will lead to advanced patient care not only in Panama City but internationally," concluded Dr. Paz Rodriguez.

Filed Under: Adult Stem Cells, Heart Disease, Heart Disease, News, Stem Cell Research, Stem Cell Therapy Tagged With: , , ,
May 16, 2010 by

Dylan’s hope (Stem Cell Therapy for Cerebral Palsy)

The possibility of using stem cells to treat cerebral palsy
has been suggested by several scientists based on the ability of these cells to:
a) stimulate regeneration of damaged nervous system tissue; b) to prevent
ongoing death of neurons; and c) to directly turn into, or "differentiate" into
neurons. This is explained in the video

http://www.youtube.com/watch?v=egRxgUXDN4Y.

One type of stem cell therapy that is currently under
investigation for cerebral palsy involves administration of cells from the
umbilical cord blood. This treatment has been the subject of much interest
because of the possibility of using cord blood from other patients. Routinely
performed outside of the United States, Dr. Joanne Kurtzburg from Duke
University has been the first to perform this treatment under the regulations of
the FDA. This recent story provides a personal description of one of the
patients treated.

In May 2009 5-year old Dylan Cain could only speak about 30
words and could not interact with family and friends. Subsequent to receiving a
cord blood transplant Dylan had a "miraculous" recovery according to parents.

"They told us at Duke that it might be months before we saw
any sign of improvement," Mother Jinger Cain said. "Just six weeks after we
returned home, he started to answer questions. His right leg straightened out a
bit, and his vocabulary has expanded amazingly."

"The speech therapist found that Dylan had progressed
5-plus months in the 3 1/2-month period of time, which means he is progressing
faster than his peers," Jinger said. "What is even more impressive is that
before the stem cells and hyperbaric treatments, he was progressing at a rate of
one month for every four months that went by, or three to four months of
development in a year, so he was consistently falling behind his peers. Now he
is progressing five times faster than before, and that has blown away his
teacher and therapists at the school he attends, as well as his doctors."

Jinger said that Dylan’s teacher in Bend told her she has
never seen a child make such gains in her 20 years of teaching.

Successes such as this case have prompted other doctors to
performed clinical trials assessing in a standardized fashion whether stem cells
actually impact cerebral palsy. Dr. James E Carroll, (706) 721-3371, of The Medical College of Georgia has recently announced initiation of a 40 patient placebo controlled trial in patients with cerebral palsy between 2-12. For more information please see the link below.

www.clinicaltrials.gov/ct2/show/NCT01072370?term=NCT01072370&rank=1

Filed Under: Adult Stem Cells, Cerebral Palsy, News, Stem Cell Research Tagged With: , ,
May 16, 2010 by

Hope for Brain Injury Victims

Traumatic brain injury (TBI) is a major health problem
caused by a sudden trauma to one or more areas of the brain. Today the
conventional method of treating patients with TBI is based on administration of
supplements to rebalance the brain’s chemistry. In the early phases of TBI
reduction of the ongoing inflammation using various antioxidants and
anti-inflammatory compounds has demonstrated some promise. Unfortunately, after
the injury has occurred there is little that can be done with the exception of
physiotherapy programs to allow the patient to cope with loss of function.

Although the traditional belief has been that once the
brain is damaged, regeneration is non-existent, recent findings suggest that
this may not be entirely true. Specific parts of the brain (subventricular
zone) have been demonstrated to contain stem cells that begin to multiply and
make new brain cells (neurons) after injury. Although this healing process is
often not potent enough to cause a robust effect that can be seen clinically,
the fact that it exists pushes scientists to find ways of amplifying it.

It was discovered more than twenty years ago that pregnant
pigs have areas of the brain in which cells multiply. The more recent finding
of brain stem cells has prompted researchers to ask whether administration of
pregnancy-related hormones can actually accelerate healing of injury brains.
Scientists at the Canadian company Stem Cell Therapeutics have shown that
administration of the hormone human chorionic gonadotrophin (the same hormone
detected by the pregnancy test) to animals with TBI can accelerate recovery. We
have previously discussed here that this company is now in clinical trials with
this approach for stroke, another type of brain injury
www.cellmedicine.com/stem-cell-therapeutics-placement.asp.

Another approach to treating TBI involves administration of
stem cells from outside of the body. This approach has previously been used for
conditions like heart failure

http://www.youtube.com/watch?v=flv0RmzPyLU , liver failure

http://www.youtube.com/watch?v=DdH6Mm4w98I , or multiple sclerosis

http://www.youtube.com/watch?v=wIcUaKZWOSE.

Recent studies have demonstrated that animals in which TBI
was induced, the administration of bone marrow stem cells results in
regeneration of damaged areas. It is currently unclear whether the stem cells
themselves are becoming new neurons, or whether the stem cells are producing an
environment in which the existing brain stem cells may exert their activity.
The University of Texas has recently completed a 10 patient clinical trial of
children with TBI treated with their own stem cells

http://www.clinicaltrials.gov/ct2/results?term=NCT00254722, however the
results have not been published yet.

One example of the potential of adult stem cells in
treatment of brain damage is illustrated in a scientific report from Russia in
which comatose patients where treated with stem cells and consciousness was
regained (Seledstove et al. Cell therapy of comatose states. Bull Exp Biol
Med. 2006 Jul;142(1):129-32).

The potential of stem cell therapy for TBI is anticipated
to be promising. Dr. Paul Breen, a specialist in TBI stated ""This new research
in stem cell research is a huge breakthrough and highly anticipated. We hope
that this could help pave the way for future research in stem cell usage for
brain trauma treatment in the coming years. If it works, it could give thousands
of people who have suffered brain injury hope of, if not a complete recovery,
then certainly a much better quality of life and a restoration of many of their
physical and mental functions. It’s a strong case in favour of continued stem
cell research."

Filed Under: Adult Stem Cells, Brain Injury, News Tagged With: , , , ,
May 13, 2010 by

Stem Cells Regrow Crucial Hearing Cells in Mice

Hearing loss is a significant problem. According to the National Institute on Deafness and Other Communication Disorders 15 percent of Americans between 20 and 69, or 26 million people, have high frequency hearing loss caused by noise. Antibiotics and genetic disorders have also been identified as causative factors.

Recently a study led by Dr. Kazuo Oshima of Stanford University in California demonstrated that it is possible to generate the cells in the ear that are responsible for hearing from two types of mouse stem cells. By treating embryonic stem cells or a similar type of stem cell generated from the skin called "induced pluripotent stem cells", with a mixture of small molecules and proteins, the scientists where able to produce hair cells. These cells are covered with bristles called stereocilia which recognize sound waves and as they bend in response to the sound waves chemical channels open, which create an electrical signal that can be carried to the brain. Although it is dogma that once the hair cells are damaged, they cannot be replaced, some studies do suggest that adult stem cells are involved in repair after injury (Lang et al. Contribution of bone marrow hematopoietic stem cells to adult mouse inner ear: mesenchymal cells and fibrocytes. J Comp Neurol. 2006 May 10;496(2):187-201).

Oshima’s team believes the current finding has several implications. In a telephone interview he stated "What we are thinking is to get human iPS cells from hearing loss patients and just try to re-make the disorder in the petri dish." He continued "This could be used to screen drugs that might cause the cells to regenerate, or to activate hibernating stem cells in the ear, he said. It may also be possible to grow the cells and inject them into the ear, but no one has developed a technique for doing this."

When asked about the future of these experiments, Dr. Oshima commented "The next step is to try using human iPS cells, but it has not worked so far".

As a third-party assessment of the findings, Dr. David Corey, a professor of neurobiology at Harvard University in Massachusetts commented that "This gives
us real hope that there might be some kind of therapy for regenerating hair cells," but on a negative note he continued "It could take a decade or more, but
it’s a possibility."

Filed Under: News, Stem Cell Research Tagged With: , , ,
May 12, 2010 by

Stem Cells Have GPS to Generate Proper Nerve Cells

One of the main questions in stem cell therapy is how the
injected cells "know" to find their way into the specific parts of the body
where they are needed. The most common example of stem cells homing is during
bone marrow transplant. In this situation donor stem cells are administered to
the recipient intravenously, but somehow they find their way to the bone marrow
of recipient, and once in the bone marrow start producing new blood cells. It
was discovered that specific cells in the bone produce a chemical signal called
stromal derived factor (SDF)-1 that acts as a homing beacon for the stem cells,
causing them to be localized in the bone marrow regardless of where they are
injected. This is explained in the video
www.youtube.com/watch?v=VJaQkYWdJ8w.

By knowing the signals involved in keeping stem cells in
the bone marrow, drugs have been made that can temporarily release them from the
bone into circulation. One example of such a drug made by Genzyme called
Mozibil. This is a small molecule that has been synthesized to act as an agent
that blocks the interaction between SDF-1 and its receptor. By blocking this
interaction, stem cells are "mobilized" to exit the bone marrow and enter
systemic circulation. Once the drug exits circulation by normal metabolism, the
stem cells home back to the bone marrow, or if there is injury in the body, some
of them localize to the damaged area.

Mozibil and similar agents are useful in situations where
one wants to collect patient stem cells without having to perform a bone marrow
aspiration, which is a painful procedure involving drilling numerous holes in
the bone of the donor. Another use of such "mobilizers" is to increase the
number of stem cells in circulation, to accelerate recovery in conditions such
as stroke or heart attack. In both of these conditions an increase in
circulating stem cells is associated with better recovery. Thus if one
artificially increases the number of stem cells in circulation by administering
agents such as Mozibil, it may be possible to see a therapeutic benefit.

While the control of stem cell homing for the bone marrow
is relatively well-known, the brain is a completely different matter. A
previously unknown factor that regulates how stem cells produce different types
of cells in different parts of the nervous system has been discovered by Stefan
Thor, professor of Developmental Biology, and graduate students Daniel Karlsson
and Magnus Baumgardt, at Linköping University in Sweden.

The scientists studied a specific stem cell in the nervous
system of the fruit fly. This stem cell is present in all segments of the
nervous system, but outside of the nervous system it is found only in the
thorax. To investigate why this cell type is not created in the stomach or head
region they manipulated the Hox genes’ activity in the fly embryo. The
investigators found out that the Hox genes in the stomach region stop stem cells
from splitting before the specific cells are produced. In contrast, the specific
nerve cells are actually produced in the head region, but the Hox genes turn
them into another, unknown, type of cell. Hox genes can thus exert their
influence both on the genes that control stem cell division behaviour and on the
genes that control the type of nerve cells that are created.

"We constantly find new regulating mechanisms, and it is
probably more difficult than previously thought to routinely use stem cells in
treating diseases and repairing organs, especially in the nervous system", says
Thor.

The regulation of stem cell homing by Hox genes has previously been demonstrated in
other systems, however this is the first time that it was found in relation to
development of the nervous system. These findings may lead to strategies for
"rewiring" neurons after injury has occurred in situations such as cerebral
palsy or stroke.

Filed Under: News, Stem Cell Research Tagged With: , , , ,
May 11, 2010 by

Transient Inhibition of Transforming Growth Factor-{beta}1 in Human Diabetic CD 34+ Cells Enhances Vascular Reparative Functions

CD34 cells are primarily known for their hematopoietic activity, which means, that they are capable of making blood cells. More recently, studies have demonstrated that a subset of CD34 cells are capable of creating new blood vessel cells called endothelial cells. The ability to made new endothelial cells is important because old/dysfunctional blood vessel cells contribute to risk of stroke or heart attack.

Numerous disease conditions can benefit from increasing the number of healthy new blood vessels. Accordingly, studies have been conducted taking out patient bone marrow cells (which contain high concentrations of CD34 cells) and administering them either intravenously or locally in order to stimulate new blood vessel formation. This procedure has been helpful in patients with advanced peripheral artery disease www.youtube.com/watch?v=OwIOL13vXQ4 , as well as in patients with heart failure
www.youtube.com/watch?v=flv0RmzPyLU. There are several companies using patient’s own bone marrow as a source of stem cell therapy after manipulation, these include Aldagen, Baxter, Amorcyte, Micromet, and Harvest-Tech.

Unfortunately there is a problem with the bone marrow cells of patients with diabetes or other inflammatory conditions: the cells don’t work as well at making new blood vessels as compared to cells of healthy patients. One of the reasons for this is believed to be high concentrations of circulating TGF-beta in the blood of type 2 diabetics. This protein is known to suppress stem cell multiplication and is associated with the body trying to inhibit inflammation.

The study discussed in the paper Bhatwadekar et al. experimentally suppressed TGF-beta in CD34 cells from diabetic patients and asked whether this could restore the ability of the CD34 cells to generate new blood vessels.

The scientists used an artificially designed inhibitor technology called "morpholino antisense oligonucleotides" to treated CD34 cells. They demonstrated >90% suppression of TGF-beta production in the cells from diabetic patients. It was found that after inhibition of TGF-beta the ability of the CD34 cells to produce new blood vessels was substantially increased. This was demonstrated in the retinal ischemia reperfusion injury model in the mouse.

At a mechanistic level it appears that the therapeutic effects of TGF-beta inhibition were associated with increased ability to migrate to area of needed. This was demonstrated by higher expression of the receptor CXCR-4.

Filed Under: Diabetes, News Tagged With: , , , ,
May 11, 2010 by

Natural Compound in Broccoli Slows Breast Cancer Stem Cells

The area of cancer stem cells is very hot. To give an
example, the pharmaceutical company GSK recently purchased the cancer stem cell
company Oncomed for more than a billion dollars, at a time when Oncomed’s cancer
stem cell-targeting drugs were not even tested in humans. This area is of great
interest because it suggests that the way to kill cancer is not to block the
fast multiplying cells, but that the cancer has a "root cause" that scientists
for decades have been ignoring.

Cancer stem cells are usually not destroyed by chemotherapy
or radiation therapy because they are slow dividing cells that possess numerous
proteins to protect themselves from toxicity such as multiple drug resistance
proteins. These proteins have the function of identifying chemotherapy inside
of the cancer cell and actively pumping it out. It is believed that the reason
why these proteins exist is to protect cells from damage to DNA. In cancer stem
cells these proteins appear to play a role in causing relapse after
chemotherapy.

Previously it was reported that the chicken feed antibiotic
salinomycin has the ability to selectively kill cancer stem cells (Gupta PB.
Identification of selective inhibitors of cancer stem cells by high-throughput
screening. Cell. 2009 Aug 21;138(4):645-59. Epub 2009 Aug 13), additionally,
using similar testing scenarios researchers found the anti-diabetic drug
metfomin inhibits breast cancer stem cells (Vazquez-Martin et al. The
anti-diabetic drug metformin suppresses self-renewal and proliferation of
trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer
Res Treat. 2010 May 11). Given the recent nature of these findings, their
use in humans has not yet been reported in the scientific literature. In the
current study which will be discussed, another compound with similar anti-breast
cancer stem cell activity was identified.

A recent study (Li et al. Sulforaphane, a dietary
component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin
Cancer Res. 2010 May 1;16(9):2580-90) demonstrated that a natural chemical
compound found in broccoli and other cruciferous vegetables called sulforaphane
has the ability to slow down multiplication of breast cancer stem cells.
Essentially this means that sulforaphane can block the cells that cause cancer
from being activated and thus could be an effective cancer therapy if high
enough doses can be safely administered.

The scientists purified human breast cancer stem cells
using the Aldefluor assay made by the company Aldagen, which selects for cells
expressing the enzyme aldehyde dehydrogenase, an enzyme found in normal and
cancer stem cells. The stem cells were tested to see if they would form tumors
in mice lacking an immune system called nonobese diabetic/severe combined
immunodeficient mice.

It was found that sulforaphane administered at a
concentration of 1-5 micromol/L was sufficient to suppress multiplication of the
aldehyde dehydrogenase-positive stem cell population by 65% to 80% and reduce
the size and number of primary mammospheres by 8- to 125-fold and 45% to 75%,
respectively. Mammospheres are round tumor-like structures that grow in tissue
culture plates that represent a three-dimensional cancer.

Daily injection with 50 mg/kg sulforaphane for 2 weeks
reduced aldehyde dehydrogenase-positive cells by >50% in nonobese
diabetic/severe combined immunodeficient xenograft tumors. Since it appeared
that the administration of sulforaphane eliminated breast cancer stem cells in
the animal, the next step was to assess the ability of the growing tumors to
cause secondary tumors when transplanted into other animals. This indeed was
demonstrated to be the case. Ability to block transfer of tumors to secondary
recipients is associated with possibility of cure since it represents targeting
of the functional tumor stem cell compartment.

Mechanistically it appears that sulforaphane works on the
cancer stem cells through suppression of the Wnt/beta-catenin self-renewal
pathway, which is found in numerous tumor and non-malignant stem cells. This of
course poses the question of whether the high doses of sulforaphane that were
used in the study would have unwanted effects on healthy stem cells in the
body. The most relevant side effect of chemotherapeutic drugs is suppression of
blood cell production from the bone marrow stem cell. Indeed the scientists
found that there was no alteration of blood cell parameters in treated animals,
suggesting at least a partial degree of selectivity.

Sulforaphane is believed to exert at least some of its
anticancer biological effects through its ability to suppress histone
deacetylase (HDAC) activity. HDAC are proteins that are involved in "bundling"
of the DNA. If DNA from one cell was stretched out, it would be 7 meters from
end-to-end. The histone that are acetylated bind DNA in a loose manner and
allow for new genes from the DNA to be expressed that normally would not be
expressed. In the area of cancer, the treatment with HDAC inhibitors is
believed to cause brand new expression of tumor suppressor genes. These genes,
such as p53, instruct the tumor cell to undergo cellular suicide, called
apoptosis.

The controversial "Burzynski Therapy" involving
antineoplastons, which are naturally occurring compounds is believed to function
through induction of histone acetylation and induction of tumor suppressor genes
(Burzynski, The present state of antineoplaston research, Integr Cancer Ther.
2004 Mar;3(1):47-58). It would be interesting to examine whether some of the
reported positive effects of this non-toxic cancer therapy is mediated by
suppression of tumor stem cell activity.

A recent paper (Ho et al. Dietary sulforaphane, a
histone deacetylase inhibitor for cancer prevention. J Nutr. 2009
Dec;139(12):2393-6. Epub 2009 Oct 7) demonstrated that sulforaphane inhibits
HDAC activity in human colorectal and prostate cancer cells. Based on the
similarity of sulforaphane metabolites and other phytochemicals to known HDAC
inhibitors, it was previously demonstrated that sulforaphane acted as an HDAC
inhibitor in the prostate, causing enhanced histone acetylation, derepression of
P21 and Bax, and induction of cell cycle arrest/apoptosis, leading to cancer
prevention. The possible ability of sulforaphane to target aberrant acetylation
patterns, in addition to effects on phase 2 enzymes, may make it an effective
agent in suppressing cancer cells in a non-toxic manner.

This study also poses the question if HDAC inhibitors in
general can alter tumor stem cell ability. It is known that valproic acid, the
HDAC inhibitor actually increases ability of stem cells to self renew while
being selectively toxic to leukemic cells

http://www.youtube.com/watch?v=3Hc4LCUOSiA.

An interesting note regarding cancer stem cells is that many approaches
traditionally supported by practitioners of alternative medicine may actually be
targeting these cells. In alternative medicine the main theme is providing the
body with nutrients to "heal itself". Practitioners of alternative medicine
have had some degree of success treating cancer in a "nontoxic" manner using
dramatic dietary modifications, nutrient therapy, and administration of agents
that induce differentiation. It may be possible that these interventions act to
reduce the localized inflammation in the tumor mass. This inflammation is
believed by some to be what stimulates the cancer stem cell to enter cell
cycle. Accordingly, it is interesting to see that components of broccoli
inhibit cancer stem cells. It will be interesting to examine other nutrients
for ability to target cancer stem cells.

Filed Under: Cancer, News, Stem Cell Research Tagged With: , , , ,
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