WINNING THE WAR ON CANCER
In the last article “Losing the War on Cancer” I discussed the current
failure of chemotherapy to turn the tide of increasing incidence of cancer. I looked
at the reasons why this was the case. I discussed the clues from Nature that suggest
that the cancer prevention actions of the phyto-nutrients in fruit and vegetables
are likely to be due to a range of nutrient-gene interactions and not just an anti-oxidant
effect. Specific phyto-nutrients decrease DNA damage, improve cell communication,
improve cell detoxification, are anti-inflammatory, boost Immunity and improve circulation
and there may be other as yet undefined actions of phyto-nutrients that are relevant
to their cancerostatic effect.
The key to unravelling the cancer mystery I believe lies in correctly identifying
the mechanisms by which a normal regulated cell becomes an “unruly”
unregulated one.
The cell is an exceedingly complicated and subtle machinery in which all functions
are carefully regulated. A normal cell divides only when division is needed. A cancer
cell divides also when no division is needed. This means that the cell regulators
are out of order. Many efforts to show the difference between the chemical makeup
of a normal and a cancer cell have hitherto failed. The cellular structures are
identical, only the regulators are disturbed. Something has gone wrong that has
to be repaired.
How does a normal cell become unregulated?
In recent years there has been a great deal of focus on the possible assaults on
a cell that may cause it to mutate and become abnormal. Does a virus or a toxin
or free radical cause damage to DNA and lead to an alteration in the cells regulatory
genes, for example those involved in normal programmed cell death. Interesting though
this is in theory, it has not led to any major solution to the cancer problem.
There have been some historical clues to suggest that a fundamental flaw that occurs
in all cancers is a disturbance in cell metabolism, that makes the cell prefer a
fermentation of glucose (using glycolysis) for energy production rather than the
more efficient oxidative metabolism (which requires oxygen and generates much more
energy). (Warburg,1930; Szent-Gyorgyi et al, 1963). It seems that this switch to
fermentation may be a mechanism for allowing cell division and therefore growth
to occur and may be the process that normally happens when the cell needs to divide.
After this normal cell division the process then reverts back to oxidative metabolism,
with its associated electron flow, and which requires a more organised cell structure.
Therefore, it may be that the uncontrolled growth of cancer cells is associated
with them being stuck in a fermentation process. We must then ask the question –
What keeps them stuck in this process? Or what turns off the ability of the cell
to revert back to a normal oxidative cell metabolism - which seems to be associated
with cell regulation?
These arguments are not new and have been presented before by Albert SzentGyorgyi,
the Hungarian-born Nobel prizewinner, in the 1950s and 60s. (Dr. Albert Szent-Gyorgyi
was the Nobel Laureate in Medicine in 1937 for the isolation and discovery of Vitamin
C. Known as the "Father of Nutritional Science", he also discovered iso-flavones
and vitamin P. In his last 40 years, he researched the regulatory processes of cell
growth, and thereby the regulation of cancer itself).
Otto Warburg in 1930, has championed the fact that anoxia is the cause of cancer
for decades. The first notable experimental induction of cancer by oxygen deficiency
was described by Goldblatt and Cameron (1953), who exposed heart fibroblasts in
tissue culture to intermittent oxygen deficiency for long periods and finally obtained
transplantable cancer cells, whereas in control cultures that were maintained without
oxygen deficiency, no cancer cells resulted. Warburg emphasizes, “but there
is only one common cause into which all other causes of cancer merge, the irreversible
injuring of respiration.” I will present evidence later that this
change in cell respiration may not be irreversible after all.
One of the many mysteries about muscles is the fact that they rarely develop cancer.
This may be because they are so dependent on oxygen and oxidative metabolism or
so rich in mitochondria, the power centers of the cell, that there is too much oxidative
reserve for cancer to develop.
It is now well accepted that most cancers are more glycolysis-dependent than normal
cells. Cancer cells have lost their capacity to conduct oxidations, and also the
mechanisms that use the energy of oxidation for useful work. Instead a low-grade
process, wasteful fermentation, is used to produce energy. As stated above, this
may be the norm for the cell when it wants to divide. Positron emission tomography
(PET) imaging has now confirmed that most malignant tumours have increased glucose
uptake and metabolism. Warburg suggested, but did not prove, that this was due to
‘‘abnormal mitochondria’’ (Warburg, 1930); that is, cancer
cells are forced to use inefficient, non-mitochondrial means of generating ATP (the
energy unit of cells). Szent-Gyorgyi was also of the opinion that this apparent
mitochondrial ‘‘dysfunction’’ is in fact reversible. It
was his research that suggested that this fermentation energy is transferred to
the mitotic mechanism, where it forces cell division. In other words as stated earlier,
efficient oxidative energy production is associated with organized cell structure,
whereas fermentation is associated with lack of structure and the inclination to
cell division. When cancer cells multiply they are merely performing an innate function.
It has been reported that human cancer cell lines have a more negative membrane
potential compared to several non-cancerous cell lines, suggesting that this might
be a hallmark of malignancy (Bonnet et al, 2007). Since a significant proportion
of cell energy production (70% or more) is channeled towards maintaining electrical
integrity by supporting the ion pumps at the cell membrane, it becomes clear that
this abnormal membrane potential of cancer cells is likely to be secondary to the
cell being “metabolically” compromised.
Mitochondrial Function and cancer
Mitochondria are the seat of energy production in the cell producing 80% of the
energy needs of the cell. Several differences have been observed between the mitochondria
of cancer cells and those of normal cells. It has been suggested that mutations
in mitochondria might cause cancer (Woods & DuBuy, 1945). More recently it has
been shown that mitochondria are integrally involved in apoptosis or programmed
cell death (Petit & Kroemer,1998; Zamzami et al, 1996). The mitochondria contain
their own DNA (less then 1% of nuclear DNA), which seems to be more susceptible
to damage and mutations than nuclear DNA. The accumulation of mutations in mitochondrial
DNA has also been suggested to play a causative role in ageing. Various tumour cell
lines exhibit differences in the number size and shape of mitochondria relative
to normal controls. The mitochondria of rapidly-growing tumours tend to be fewer
in number, smaller and have fewer internal folds than mitochondria of slowly growing
tumours. Alterations in the inner membrane composition of tumour mitochondria have
also been noted (Modica-Napolitano & Singh, 2002). The mitochondrial membrane
potential of cancer cells is approximately 60mV higher than that of control epithelial
cells (Modica-Napolitano & Aprille, 1987). Mitochondrial dysfunction is one
of the most profound features of cancer cells.
Cancer progression and its resistance to treatment depend, at least in part, on
suppression of apoptosis (programmed cell death). As stated above, mitochondria
are recognized as regulators of apoptosis.
We have already established that cancer seems to be associated with a glycolytic
phenotype. Furthermore, it appears that glycolytic phenotype is indeed associated
with a state of apoptosis resistance (Plas and Thompson, 2002). Many glycolytic
enzymes have been recognized to also regulate apoptosis, and several oncoproteins
induce the expression of glycolytic enzymes (Kim and Dang, 2005).
All the available evidence suggests that if we want to understand cancer better and
find a remedy then we have to turn our attention specifically to mitochondria, for
it is here that the energy malfunctions that occur in cancer are to be found.
Mitochondrial changes have multiple downstream effects, beyond energy production,
because mitochondria regulate several critical functions including calcium concentration
and free radical (Reactive Oxygen Species, ROS)-redox control. Mitochondria have
an important role in apoptosis that may explain the apoptosis resistance that occurs
in many human cancers.
Cancer cells have been shown to have more hyperpolarized mitochondria and were relatively
deficient in potassium channels. If this metabolic-electrical remodelling is an
adaptive response, then its reversal might increase apoptosis and inhibit cancer
growth. The Michelakis research group showed that dichloroacetate (DCA), a small,
orally available small molecule and a well-characterized inhibitor of the key enzyme
in the glycolytic chain, pyruvate dehydrogenase, was able to change the metabolism
of cancer cells from the cytoplasm-based glycolysis to the mitochondria-based glucose
oxidation. DCA also reversed the inhibition of potassium channels in all cancer,
but not normal cells. The net effect was a reversal of resistance to apoptosis (Bonnet
et al, 2007). DCA treatment significantly increases glucose oxidation (which only
occurs in functional mitochondria), indicating that the metabolic cancer signature
(aerobic glycolysis) is reversible, rather than a consequence of permanent mitochondrial
damage. Szent-Gyorgyi concluded this but this was also the conclusion of Koch (1958,
see below) whose work strongly suggested that the metabolic/mitochondrial abnormality
in cancers could be reversed. DCA was shown to significantly decrease tumour growth
in rats without toxic effects. At this time, though approved as a drug treatment
for mitochondrial diseases in humans, and apart from anecdotal reports, there are
no formal clinical trials in patients with cancer.
Dr. William Koch’s research (1958) focused on the means to restore the body’s
oxidation mechanism back to its original vitality, thereby re-equipping the body
with its innate ability to restore and maintain health, not only in cancers but
also in a host of other diseases.
Organized Medicine launched a fifty-year assault aimed at discrediting Dr. Koch’s
reputation, medical practice and research, along with those of any physician who
dared to validate his Theories or use his Reagents. Dr Koch’s theories emphasized
the relationship between environmental toxins, dietary deficiencies and a depleted
oxidation mechanism, as primary initiators of the disease process. In his work he
discovered that removal of the parathyroid gland of animals led to accumulation
of toxic substances in the body. He also observed that the urine of the animals
without parathyroid glands carried large amounts of lactic acid, which meant that
the oxidation process was badly handicapped by the substances that were produced
in the parathyroidectomized animals. These substances had blocked the normal tissue
oxidation process. This turned out to be a momentous discovery, which paved the
way for his original cancer research. By studying the tissues that survived the
longest, he found out that the common feature was the presence of the di-carbonyl
groups. He postulated that the toxic amines of various metabolic, bacterial, viral
or of fungal agents (present day antibiotics included) are able to cripple these
important carbonyls by condensing with them. These functional carbonyls were crucial
to the preservation of electron transport and metabolic function of the cell but
when they were complexed by toxins this could lead to an irreversible compromise
of metabolic function. Unfortunately Dr. Koch was never given the research facilities
and cooperation by the medical profession he had asked for and wanted.
Despite several cases of advanced cancers being treated successfully by Koch (by
the injection of carbonyl compounds) in 1919 under the auspices of the Wayne County
Medical Society branch of the American Medical Association (AMA), the Journal of
the A.M.A. published over 20 negative editorials and articles about Dr. Koch and
his treatment dating back to February 12, 1921.
In 1968, Dr. Szent-Gyorgyi also wrote about the cancerostatic action of carbonyl
compounds (Szent-Gyorgyi et al, 1967) and how they are able to arrest cell division.
He described these substances in urine and also in tissue extracts from several
body organs. His research suggested that these substances when present are not only
able to inhibit cell proliferation but also to maintain cells in a normal oxidative
metabolism. The suggestion is that the body can lose its ability or become compromised
in its ability to produce these substances thereby encouraging the development of
cancer.
Further evidence that compromised mitochondrial function is a fundamental cause
of the development of cancer is also suggested by the reported efficacy of the Kucera
cancer support regime. Dr Michael Kucera, a Czech physician, has spent 20 years
or more researching mitochondrial medicine and has developed a nutritional combinations
for mitochondrial support (Personal communication, 2009). A combination of these
nutrients with specific immune support nutrients has led to remarkable success in
cancer remissions. Over 700 cancer patients have been treated with this regime during
the last 10 years. These have been patients with variable cancers, most of them
non-localised i.e. they have already spread (including breast, prostate, colon and
gastric cancers). Overall a 70% remission at 5 years is reported and an 80-90% remission
when the formulas are combined with chemotherapy. No side effects were observed.
Compare this to the efficacy of chemotherapy of 2-3% and with significant side effects.
To my knowledge this may be the most effective treatment regime available and is
the regime of choice used in my own clinic. It is even more remarkable that the
regime is a purely oral-based regime. The fundamental basis for this high level
of efficacy must be due to the core benefit to the mitochondria.
Coenzyme Q10 will be more familiar to many of you. This fat-soluble substance is
present in most eukaryotic cells, primarily in the mitochondria. It is a component
of the electron transport chain and participates in aerobic cellular respiration,
generating energy in the form of ATP. Ninety-five percent of the human body’s
energy is generated this way (Ernster & Dallner, 1995; Dutton et al, 2000) Therefore,
those organs with the highest energy requirements—such as the heart and the
liver—have the highest CoQ10 concentrations (Okamato et al, 1989; Aberg et
al, 1992; Shindo et al, 1994).
Interest in coenzyme Q10 as a potential therapeutic agent in cancer was stimulated
by an observational study that found that individuals with lung, pancreas,
and especially breast cancer were more likely to have low plasma coenzyme Q10 levels
than healthy controls (Folkers et al, 1997). There are a few case reports and an
uncontrolled trial (see below) suggesting that coenzyme Q10 supplementation may
be beneficial as an adjunct to conventional therapy for breast cancer (Hodges et
al, 1999).
Although CoQ10 is best documented in the treatment of heart failure, two medical
journal articles suggest tremendous promise in the treatment of cancer. Folkers
(1997) described 10 cancer patients given CoQ10 for heart failure. One of the patients,
a 48-year-old man diagnosed with inoperable lung cancer, had no signs of either
cancer and heart failure symptoms while taking CoQ10 for 17 years.
Knud Lockwood, M.D (1994), a cancer specialist in Copenhagen, Denmark, described
his treatment of 32 "high-risk" breast cancer patients with antioxidant vitamins,
essential fatty acids, and CoQ10. "No patient died and all expressed a feeling of
well-being," he wrote "These clinical results are remarkable …..After 24
months, all still survived; about 6 deaths would have been expected." Six of the
32 patients showed partial tumour remission, and two benefited from very high doses
of CoQ10. One, a 59-year-old woman with a family history of breast cancer, had a
tumour tumour recurrence 1.5-2 centimetres in diameter but one month after increasing
the CoQ10 intake to 390 mg. daily, the tumour had disappeared. Mammography confirmed
its absence. Another patient, age 74, had a small tumour removed from her right
breast. She refused a second operation to remove additional growths and began taking
300 mg of CoQ10 daily. Three months later, an examination and mammography revealed
no evidence of the tumour or metastases. Lockwood, who has apparently treated some
7,000 cases of breast cancer over 35 years, wrote that until using CoQ10, he had
"never seen a spontaneous complete regression of a 1.5-2.0 centimetre breast tumour,
and has never seen a comparable regression on any conventional anti-tumour therapy."
Although none of the above are controlled studies they provide circumstantial evidence
for my hypothesis that mitochondrial metabolic malfunction are critical to cancer
development and should be the primary target in the war against cancer. Indeed,
I have presented evidence from several pioneering doctors/researchers to show that
when the mitochondria are supported and/or their metabolic defect is corrected that
this is associated with cancer remissions. I am not the first to suggest this but
I cannot ignore the evidence before me. I am convinced that this is the key to unravelling
the cancer mystery. History has given us the clues…..it is time to stop ignoring
them!
It was not the purpose of this article to focus on anything but the physical side
of treatment but it would be an omission in the context of the title of this article
“Winning the war on cancer” not to at least comment on the role of belief
and positive thought to influence positive outcome in the war. This important component
has been discussed elsewhere (Byrne, 2006; Chopra, 1989).
References
|
Aberg,F.et al. Archives of Biochemistry and Biophysics.1992, 295, 230-234
|
|
Bonnet,S; Archer, SL; Allalunis-Turner,J Haromy, A; Beaulieu,C; Thompson,R; Lee,CT;.
Lopaschuk, GD; Puttagunta,; Bonnet, S; Harry, G; Hashimoto, K; Porter, CJ; Andrade,
MA; Thebaud, B and Michelakis, ED. A Mitochondria-K+ Channel Axis Is Suppressed
in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth. Cancer
Cell, 2007, 11, 37–51.
|
|
Byrne, R. The Secret. 2006. Simon & Schuster Ltd Chopra, D. Quantum Healing: Exploring
the Frontiers of Mind/Body medicine. Bantam books, New York, 1989
|
|
Dutton PL, Ohnishi T, Darrouzet E, Leonard, MA, Sharp RE, Cibney BR, Daldal F and
Moser CC. 4 Coenzyme Q oxidation reduction reactions in mitochondrial electron transport
(pp 65- 82) in Coenzyme Q: Molecular mechanisms in health and disease edited by
Kagan VE and Quinn PJ, CRC Press (2000), Boca Rat
|
|
Ernster L, Dallner G: Biochemical, physiological and medical aspects of ubiquinone
function. Biochim Biophys Acta 1995,1271: 195-204,
|
|
Folkers K, Osterborg A, Nylander M, Morita M, Mellstedt H. Activities of vitamin
Q10 in animal models and a serious deficiency in patients with cancer. Biochem Biophys
Res Commun. 1997;234(2):296-299.
|
|
Goldblatt, H; and Cameron, G. Induced Malignancy In Cells From Rat Myocardium Subjected
To Intermittent Anaerobiosis During Long Propagation In Vitro. The Journal of Experimental
Medicine, 1953, 97, 525-552.
|
|
Hegyeli, A; McLaughlin, JA; Szent-Gyorgi, A. Preparation of Retine from Human Urine.
Science: 1963, 142, 1571-1572
|
|
Hodges S, Hertz N, Lockwood K, Lister R. CoQ10: could it have a role in cancer management?
Biofactors.1999;9(2-4):365-370.
|
|
Kim, JW and Dang, CV. Multifaceted roles of glycolytic enzymes. Trends Biochem.
Sci. 2005, 30, 142–150.
|
|
Koch, WF. 1958. The Survival Factor in Neoplastic and Viral Disease.
|
|
Lockwood, K. Biochemical and Biophysical Research Communications.1994,199, 1504-8
|
|
Modica-Napolitano, JS & Aprille, JR. Basis for the selective cytotoxicity of rhodamine
123. Cancer Res, 1987, 47, 4361-4365
|
|
Modica-Napolitano, JS & Singh, KK. Mitochondria as Targets for Detection and Treatment
of Cancer. Expert Reviews in Molecular Medicine. www-ermm.cbcu.cam.ac.uk. 2002, pp1- 19
|
|
Okamoto, T.et al. Interna.J.Vit.Nutr.Res.1989,59,288-292
|
|
Petit, PX & Kroemer, G. Mitochondrial regulation of apoptosis. In Mitochondrial
DNA Mutations in Aging, Disease and Cancer (Singh KK ed), pp147-165, Springer-Veerlag,
Berlin 7 Plas, DR., and Thompson, CB. Cell metabolism in the regulation of programmed
cell death. Trends Endocrinol. Metab, 2002, 13, 75–78.
|
|
Shindo, Y., Witt, E., Han, D., Epstein, W., and Packer, L., Enzymic and non-enzymic
antioxidants in epidermis and dermis of human skin, Invest. Dermatol. 1994,102,
122-124.
|
|
Szent-Gyorgi, A. Bioelectronics and Cancer. Bioenergetics, 1973, 4, 533-562
|
|
Szent-Gyorgi, A; Egyud LG; McLaughlin, JA. Keto- Aldehydes and Cell Division. Science:
1967, 155, 539-541
|
|
Szent-Gyorgi, A; Hegyeli, A; McLaughlin, JA. Cancer Therapy: A Possible New Approach.
Science: 1963, 140, 1391-1392
|
|
Warburg, O.1930. Metabolism of Tumours. (London: Constable).
|
|
Woods, MW & DuBuy, HG. Cytoplasmic diseases and cancer. Science: 1945,102, 591-593
|
|
Zamzami, N et al. Mitochondrial control of nuclear apoptosis. J Exp Med, 1996, 183,
1533- 1544
|
|
