I read this article while surfing through my Facebook page, which is what I find myself doing a lot because of my battle with Chronic Pain. I am at home a lot, mostly stuck in bed on a heating pad after 10 years of trying to get a proper diagnosis and proper treatment and battling with doctors and discrimination and mistreatment.
The subject of this story is not related to Chronic Pain but I find the struggle the same: doctors do not always have YOUR best interest at heart.
I also related to the story of Gina Crosley-Corcoran and the birth of her son Jules because I am a new mother with a 3 month old baby and I made a decision to let my doctor induce labor for the ridiculous reasoning that the baby was getting too big.
The idea is the same. Knowledge is power when it comes to your own medical care, whether that be the desire to experience a vaginal birth after having a C-Section or advocating for the best care for chronic pain in spite of being a recovering addict.
Here is the story of Gina and her husband John and what they had to go through to fight for the most natural thing a woman’s body can do on its own if you allow it to happen.
This was something that I did not want to blog about at face value. I typed the drug name into Google Scholar to see what primary literature I could find on the subject. Here is some real information I have found:
Received 18 December 2007; Revised 28 April 2008; Accepted 4 July 2008; Published online 2 September 2008.
“The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function.
The generic drug dichloroacetate is an orally available small molecule that… increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis.”
Abstract: “The invention relates to the use of dichloroacetate and chemical equivalents thereof for the treatment of cancer by inducing apoptosis or reversing apoptosis-resistance in a cell Preferably, the dosage is 10-100 mg/kg Preferably, sodium dichloroacetate is used. The dichloroacetate may optionally be given in combination with a pro-apoptotic agent and/or a chemotherapeutic agent Preferably, the cancers treated are non-small cell lung cancer, glioblastoma and breast carcinoma.”
Inventors: Michelakis, Evangelos (Edmonton, CA)
Archer, Stephen (La Grange, IL, US)
International Classes: A61K31/19; A61B5/00; A61P35/00; A61K31/185; A61B5/00; A61P35/00
This patent application claims priority from U.S. Provisional Patent Application No. 60/669,884 filed Apr. 11, 2005, the content of which is hereby incorporated by reference herein.
FIELD OF THE INVENTION
The invention relates to the use of dichloroacetate and obvious chemical equivalents thereof in the treatment of cancer. Related uses and diagnostic and screening methods are also included in one aspect of the present invention.
BACKGROUND OF THE INVENTION
Most cancers are characterized by a resistance to apoptosis that makes them prone to proliferation and resistant to most cancer therapies. Most of the available cancer treatments aim to induce apoptosis but are highly toxic. There are two main categories of apoptosis: the receptor-mediated and the mitochondria-dependent apoptosis. Mitochondria-dependent apoptosis is not very well studied and only recently have the mitochondria been viewed as anything more than an organelle that produces energy. As such there is a need for a cancer therapy that can overcome apoptosis resistance in cancer cells.
SUMMARY OF THE INVENTION
A cell can become resistant to apoptosis in a variety of ways one of which is altering its metabolism and having hyperpolarized mitochondria. Since apoptosis is initiated by depolarization of mitochondria, the more hyperpolarized a mitochondrion is, the further it is from the depolarization threshold and the more resistant it is to the initiation of apoptosis.
In one embodiment the present inventors have surprisingly found that one can modulate mitochondrial function to treat cancer. In one embodiment, the present invention provides a method for inducing apoptosis in cancer. In another embodiment, the inventors provide a method for inducting apoptosis in cancer but normal cells. In another embodiment, the invention provides a method of reversing apoptosis resistance in cancer cells, such as cancer cells with hyperpolarized mitochondria. In one embodiment, the method comprises administering to cancer cells, in one embodiment cells having or suspected of having hyperpolarized mitochondria, an effective amount of dichloroacetate or salts thereof or obvious chemical equivalents thereof.
In one embodiment, the dichloroacetate or obvious chemical equivalent thereof is administered in combination with another pro-apoptotic agent and/or chemotherapeutic agent, and/or other cancer therapy.
In one embodiment, the invention provides a method for inducing apoptosis and/or reversing apoptosis resistance in a cancer cell, comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method for inhibiting proliferation of cancer cells, comprising administering to the cells an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of decreasing survivin in a cancer cell, comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing Kv1.5 protein in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing AIF in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a method of increasing H 2 O 2 in a cancer cell comprising administering to the cell an effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the methods of the invention cancer cells, but not normal or non-cancerous cells are affected by the treatment with dichloroacetate or obvious chemical equivalent thereof.
In one embodiment, the present invention provides a method for treating a cancer. In another embodiment, the invention provides a method of treating a cancer associated with hyperpolarized mitochondria. In another embodiment the invention provides a method of treating cancer by restoring mitochondrial membrane potential (ΔΨm) (essentially depolarizing the hyperpolarized cancer cell mitochondria). This molecular metabolic therapy is accomplished by administering to a patient in need thereof a therapeutically effective amount of dichloroacetate or obvious chemical equivalent thereof. In another embodiment, the invention provides a use of dichloroacetate or obvious chemical equivalent thereof in the treatment of cancer.
In one embodiment, the dichloroacetate is a salt of dichloroacetic acid. In another embodiment, the dichloroacetic acid is a sodium salt of dichloroacetic acid.
In one embodiment, the cancer to be treated using the DCA or obvious chemical equivalent thereof is selected from the group consisting of: non-small cell lung cancer, glioblastoma and breast carcinoma.
In another embodiment, the dichloroacetate, or obvious chemical equivalent thereof, is administered in the form of a pharmaceutical composition comprising dichloroacetate or obvious chemical equivalent thereof and a pharmaceutically acceptable carrier. In yet another embodiment the invention provides a use of dichloroacetic acid or dichloroacetate or obvious chemical equivalent thereof in the preparation of a medicament or pharmaceutical composition for the treatment of cancer, such as a cancer associated with hyperpolarized mitochondria. In yet another embodiment, the dichloroacetate, or obvious chemical equivalent thereof, is administered orally.
In yet another embodiment, the dichloroacetate is administered in a water-based formulation. In one embodiment the water-based formulation of DCA comprises 0.0075 g of DCA/l to 7.5 g of DCA/l). In another embodiment the dichloroacetate or obvious chemical equivalent thereof is administered at a total daily dose of ˜25-50 mg/kg bid of dichloroacetate. In another embodiment the dose is 10-100 mg/kg given twice a day is administered to the patient. In one embodiment the dose is 25-50 mg bid.
In another embodiment, the invention constitutes a method for determining whether a cancer is associated with hyperpolarized mitochondria, which would predict its therapeutic response to dichloroacetate or obvious chemical equivalents thereof or similar compounds. In one embodiment such method comprises administering an effective amount of dichloroacetate, or chemical equivalent thereof to a cancer tissue sample from a patient and measuring its apoptosis sensitivity and mitochondrial membrane potential using confocal microscopy or flow cytometry. This diagnostic test would determine whether the individual patient could benefit from dichloroacetate or other therapies that cause apoptosis through similar mechanism.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
For several years now, the U.S. Senate has proclaimed the third Friday in May to be Endangered Species Day. This year, the day has extra significance. The Endangered Species Act (the only thing standing between countless species and extinction) has come under unprecedented attack.
To paraphrase John Donne, “No species is an island.” Humans, too, depend on biodiversity and the richness of the web of life. Aldo Leopold, compared the loss of species to “throwing away, one-by-one, the engine parts of an airplane while flying.”
What’s more, the airplane’s facing some serious turbulence. All living things — including humans — face new and daunting challenges in a world where the climate has been disrupted. Habitats are shifting and pressures on species are increasing. You can’t preserve that web of life without also protecting the places it lives. We might think we’re protecting habitat for this or that creature — but in truth we’re doing it for all living things, not least ourselves. That’s the basis for the Sierra Club’s Resilient Habitats campaign, which is working to protect places where plants, animals, and people can survive and thrive.
While the National Marine Fisheries Service has declared an Unusual Mortality Event (UME) in the Northern Gulf of Mexico, it’s more than just oil spills that are causing increased strandings worldwide.
The occurences of beachings has increased. It could be any number of things at this point from nutrition to sonar throwing them off their intended path. The BP oil spill is a possible cause but might not be the only one.
NOAA provides this chart of whale strandings in the Gulf of Mexico, showing the marked increase:
Speculations continue. It is still very uncertain as to why this is happening in different parts of the world.
Spring is the perfect time to plant trees. And establishing a streamside forested buffer will not only help protect water quality, it will attract wildlife by providing much-needed habitat. The Conservation Reserve Enhancement Program (CREP), a federally funded program, provides landowners and farmers with the resources to design and install these buffers. CREP also pays annual rental payments to the landowner.
There are many benefits to forested buffers, including preventing pollutants from reaching streams, creating wildlife habitat, and improving water quality. Streamside trees also help reduce stormwater and flooding problems by slowing down and absorbing rainwater as it moves across the land. Buffers also provide recreational opportunities like wildlife and bird watching, and they improve property values.
The Conservation Reserve Enhancement Program (CREP) is a voluntary conservation program which rewards producers and landowners for installing conservation practices on their land, and offers up to 100% cost share reimbursement for installation, annual rental payments, and cash incentives.
Highly Erodible Land (HEL) – Land susceptible to erosion (usually found on steep slopes, but depends on soil type and vegetative cover).
Marginal Pastureland – Land near a stream or water body not currently covered with trees or woody growth.
Riparian Zone – Land adjacent to stream channels and other waterways.
Riparian Buffer – Strips of trees, shrubs and/or grasses along the edges of waterways that stabilize banks and filter runoff.
Wetland – An area that frequently is inundated by surface and/or groundwater, providing a unique habitat for wildlife, improving water quality and protecting against floods. A wetland is different than a pond.
Shallow Water Area – A source of water with an average depth of 6 – 18 inches which provides wildlife habitat.
Native Grasses – Warm and cool season grasses naturally occur in western PA. Warm season grasses include indiangrass, big bluestem, and switchgrass. Cool season grasses include orchardgrass, timothy and perennial ryegrasss.
A variety of wildlife depends on grassland habitats and adjacent riparian areas year-round. Birds use the many layers of vegetation cover (trees, shrubs, and grasses) and plentiful plant species found in these habitats for food and cover. During the breeding season, many ground-nesting bird and mammal species build nests in the vegetation and use the cover to raise and protect their young. In the winter, seeds are foraged and dead vegetation creates pockets where ground-dwelling birds can take shelter. Butterflies, and other enjoyable insects, feed on the flowers that grow in the grassland. Unlike the specific vegetation of riparian corridors, wetlands, and grasslands, the wildlife that depend on these areas commonly travel between them for both food and shelter.
Global warming has already harmed the world’s food production and has driven up food prices by as much as 20% over recent decades, new research has revealed.
An Indian farmer displays wheat after harvest on the outskirts of Jammu, India, Thursday, May 5, 2011. Global warming has already harmed the world’s food production and has driven up food prices by as much as 20% over recent decades, new research has revealed. (AP Photo/Channi Anand) The drop in the productivity of crop plants around the world was not caused by changes in rainfall but was because higher temperatures can cause dehydration, prevent pollination and lead to slowed photosynthesis.
Lester Brown, president of the Earth Policy Institute, Washington DC, said the findings indicate a turning point: “Agriculture as it exists today evolved over 11,000 years of reasonably stable climate, but that climate system is no more.” Adaptation is difficult because our knowledge of the future is not strong enough to drive new investments, he said, “so we just keep going, hoping for the best.”
“It is vital,” said Wolfram Schlenker, at Columbia University in New York and one of the research team. “If we continue to have the same seed varieties and temperatures continue to rise, then food prices will rise further. [Addressing] that is the big question.”
“We actually have enough calories to feed the world quite comfortably, the problem is meat is really inefficient,” as many kilogrammes of grain are needed to produce one kilogramme of meat, he said. “As countries get richer and have a preference for meat, which is more expensive, they price people in poorer countries out of the market.”
Global food prices have risen by about 200% in recent years, says Schlenker. Other causes of the rise are the increased demand for meat and the diversion of food into biofuels. Nonetheless, the researchers conclude that the negative impact on crops overall is “likely to be incurring large economic and health costs”.
Grassroots groups 350.org and 1Sky today announced they will combine under the 350.org banner and dramatically expand their work. “In light of last night’s vote, it is more important than ever to unite and train a bigger, more powerful grassroots movement capable of attacking our corporate polluter opponents and fighting for a real clean energy future. This moment is our call to action,” said Liz Butler, Campaign Director of 1Sky.
In an essay announcing the merger, McKibben and new 350.org board member, author and activist Naomi Klein, wrote, “The idea is not to supplant the Washington green groups, but instead to give the whole movement new clout—enough clout to withstand the crushing power of oil money.”