Literature review

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Running Head: Doxorubicin-Induced Cardiotoxicity
Effects of Calorie Restriction on Acute Doxorubicin-Induced Cardiotoxicity
Katherine Remmerde
Research Mentor: Noah Gibson
Frontiers of Science Institute, 2011
University of Northern Colorado
Summer 2011

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Abstract
In the modern health care and medical systems, cancer is a widely researched
disease because it is one of the most difficult diseases to treat and is also one of the most
common diseases worldwide. Many times with cancer treatment, specifically with
chemotherapy, the drug used to treat the cancer can become more dangerous than the
cancer itself. Cardiotoxicity is a fatal side effect of anthracycline chemotherapy; attempts
to reduce cardiotoxicity in heart tissue are one of the many purposes of cancer research as
reducing cardiotoxicity can improve the chances of chemotherapy survivorship. It is
hypothesized that calorie restriction may be able to reduce cardiotoxicity in
chemotherapeutic treatments by reducing the amount ofdamage incurred to the heart tissue
and therefore increasing survival rates of cancer patients. The experiment consisted of
calorie restricting rats and then analyzing left ventricle tissue for malondialdehyde content
to determine if calorie restriction does reduce the amount of heart tissue damage. Results
showed no signigicant difference between the groups of interest, AL_DOX and CR_DOX.
However, this may be attributed to a small sample size, and future research may show that
CR does reduce cardiotoxicity.
Key Terms
Cardiotoxicity, Doxorubicin, calorie restriction, malondialdehyde, anthracyclines,
chemotherapy, cancer, cardiomyopathy, cardiomyocytes, ad libitum, lipid peroxidation.

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Introduction
As the human species progresses and advances, increasing amounts of problems,
solutions, and subsequent questions arise. Many diseases and ailments have been on Earth
for centuries but are just now being understood. One such ailment is cancer. Cancer was
thought to be first documented in Egypt, and first classified by a Greek physician by the
name of Hippocrates. (Fayed, Cancer History). As time progressed, more research was
conducted; the circulatory system and lymph system were discovered, and later, the cell
theory arose. Now, in the 21st century, new treatments and novel research are quickly
uncovering previously dark corners of the medical world.
Cancer is a highly analyzed and investigated topic as it affects people all over the
world and so often. Some types of cancer are actually curable depending on the type of
tumor, age at which detected and or treated, how it arose, where it is located, etc. Common
types of cancer include; Bladder, Breast, Colon and Rectal, Leukemia, Lung, Skin,
Prostate, Melanoma, and Thyroid Cancer. (A to Z List of Cancers, Common Cancer Types,
National Cancer Institute). By the same token, many are not curable, and still kill millions
of people across the globe, accounting for 7.6 million deaths (13% of total) in 2008 (World
Health Organization, 2011; GLOBOCAN: Country Fast Stat., 2008). However, just as
many people are working to prevent or treat cancer. Many new, ground-breaking
experiments (e.g. Wonders, Hydock, Hayward, 2011; Hursting, S., Lavigne, J., Berrigan,
D., Perkins, S., & Barrett, J. C., 2003; Cardinale, D., et al. 2006; Shelton, L., Huysentruyt,
L., Mukherjee, P., Seyfried, T., 2010) are being conducted in the medical field concerning
cancer, and often times with this type of research a treatment is known, but not the
mechanism by which it works (Helibronn, L, & Ravussin, E., 2003). By understanding the

4
mechanism and reasons that a certain process works, it can be replicated and/or effectively
used in other areas.
The purpose of this study is to explore and analyze interventions that may decrease
the deleterious side effects of cancer treatment. Types of treatment include chemotherapy,
radiation therapy, surgery, and other alternative methods of treatment. (Types of
Treatment, National Cancer Institute). A commonly used chemotherapeutic drug is
doxorubicin; while doxorubicin is a highly effective chemotherapeutic drug, its cardiotoxic
(heart damaging) side effects can be fatal. (Singal, P., & Iliskovic, N.,1998). Many
interventions have been investigated that may decrease the cardio toxicity caused by DOX
treatment. (Chicco, A., Hydock, D., Schneider, C., & Hayward, R. 2005; Chicco, A.,
Schneider, C., & Hayward, R. 2005; Oliveiraa, P., Bjorkb, J., Santosa, M., Leinoc, R.,
Frobergd, M., Morenoa, A., et al. 2004). The process of calorie restriction (CR) is being
evaluated in order to determine if it may or may not decrease the unwanted side effects of
DOX. (Hursting, S., et al, 2003; Shelton, L., et al, 2010). Calorie restriction is a process
that reduces the amount of caloric intake in a diet by simply eating less food and or foods
with less caloric content without the onset of malnutrition. This is thought to help body
health in general because CR produces free radicals, which damage cells and DNA.
(Koubova, J., & Guarente, L. 2003).
For the experiment, rats will be calorie restricted; it is theorized that less reactive
oxygen species (chemically reactive molecules due to unpaired valance electrons in outer
shell whichcan cause damage to cells, also called ROS) will be produced from degradation
of polyunsaturated lipids, also called lipid peroxidation. (Koubova, J., & Guarente, L.
2003; Marnett, L. 1999). Lipid peroxidation produces malondialdehyde (an organic

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compound that is a marker for oxidative stress, also called MDA). (Marnett, L. 1999). The
levels of MDA will be assessed by using a spectrophotometer, which measures reflection
or transmission properties of a material as a function of wavelength. The different levels of
MDA in the 4 different experimental groups will be compared in order to determine
significant differences.
It was hypothesized that the reduced caloric intake will directly affect the amount
of ROS produced and will therefore reduce the amount of MDA in rat heart tissue. The
hypothesis should lead to reductions in doxorubicin-induced cardiotoxicity due to an
overall decrease in oxidative stress (imbalance between production of ROS and
detoxification of such) during chemotherapy treatments. Predisposing and preventing
patients from developing cardiotoxicity during chemotheraputic treatments will
dramatically increase the rates of cancer survivorship and quality of life.
Literature Review
Cancer is an invasive and detrimental disease that is often hard to treat, especially
when it metastasizes (breaks off from original growth point). Of course, treatment for these
types of worldwide diseases is common. There are multiple types of cancer treatments in
the medical field (e.g. chemotherapy, radiation therapy, surgery, and other alternative
methods of treatment). (Types of Treatment, National Cancer Institute). Chemotherapy
specifically has been utilized since World War II in treating cancer, and is now effective
for many different types of cancer. Within chemotherapy, there are many classes of drugs
used according to their effectiveness, mechanisms, and types of cancer they treat.
(American Cancer Society, 2011).

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Cancer Treatments
Alkylating agents directly damage DNA to prevent the cancer cell from
reproducing. (American Cancer Society, 2011). Antimetabolites are a class of drugs that
interfere with DNA and RNA growth during the S phase of mitosis.(American Cancer
Society, 2011). Topoisomerase inhibitors interfere with topoisomerases that separate
strands of DNA, preventing them from being copied. (American Cancer Society, 2011).
Mitotic inhibitors can stop mitosis or inhibit enzymes from making proteins needed for cell
reproduction. (American Cancer Society, 2011). Corticosteroids are hormones that can kill
or slow growth of cancer cells.(American Cancer Society, 2011). Anthracyclines are
anti-tumor antibiotics that interfere with enzymes involved in DNA replication, and can
interfere in all phases of the cell cycle, making them very effective against a growing
tumor. (American Cancer Society, 2011).
The two compounds that became the first Anthracyclines were Doxorubicin and
Daunorubicin (first derived from second). (Daunorubicin: MedlinePlus Drug Information;
Doxorubicin: MedlinePlus Drug Information). Both daunorubicin and doxorubicin are
known for their often fatal cardiotoxic side effects. Cardiotoxicity is characterized by an
increase in ROS, inflammation and mitochondrial dysfuntion, which ultimately leads to
apoptosis and cell necrosis, causing heart failure (cardiomyopathy). However,
daunorubicin in comparison with doxorubicin is less effective but also less cardiotoxic.
Daunorubicin only treats a small range of cancers such as acute leukemias whereas
doxorubicin treats a wide range of cancers suchas hematological malignancies, carcinoma,
soft tissue sarcomas, breast and ovarian cancer, etc. (Daunorubicin: MedlinePlus Drug
Information; Doxorubicin: MedlinePlus Drug Information).

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Doxorubicin, also called Adriamycin, is a cancer chemotherapy drug within the
class of anthracyclines widely used for many types of cancers due of its effectiveness in a
large number of patients (Weiss, R., 1992). Doxorubicin is a cell-cycle specific drug which
means that it often targets cells that are rapidly dividing; however, doxorubicin also affects
DNA transcription (Šimùnek, T, et al, 2009; Szuławska, & Czyż, 2006). This drug is a type
of DNA intercalator, which inhibits DNA replication (specifically topoisomerase 2), a
good strategy to stop growing cancer cells. It does this by binding to base pairs and
preventing the topoisomerase from resealing itself after initially being cut. (Szuławska,
Czyż, 2006; Šimùnek, T, et al, 2009). This process is very effective, but the specific
bonding to base pairs is likely not a major mechanism of the stop of cancer growth while
the topoisomerase 2 inhibitor is (Szuławska, Czyż, 2006). Often, these processes induce
apoptosis.
Doxorubicin reacts with iron in the blood to create reactive oxygen species and
MDA. The doxorubicin enters the body and is changed into a semiquinone by the addition
of an electron to its outer ring. (Singal, P., & Iliskovic, N. 1998; Marnet, L., 1999). In
normal oxygen levels the semiquinone gives its extra electron to oxygen creating a
superoxideradical. (Marnet, L., 1999). The semiquinones then keep receiving electrons
from flavoproteins, a certain type of protein that takes electrons from NADH and NADPH
and gives them to the semiquinones. (Singal, P., & Iliskovic, N. 1998; Marnet, L., 1999).
These superoxide radicals circulate around the body and steal electrons from these lipids in
the cell membrane (Singal, P., & Iliskovic, N. 1998; Marnet, L., 1999). This damages the
cell’s membrane and it also creates MDA, which then causes damage to surrounding
cardiomyocytes (cardiac cells) and their DNA, ending in cardiotoxicity and or

8
cardiomyopathy (heart failure) (Singal, P., & Iliskovic, N. 1998; Marnet, L., 1999).
Mitochondria in individual cells have an increasingly hard time producing ATP via
oxidative phosphorylation due to the unwanted inhibition of enzymes that carry out this
process (Gredilla, R, Sanz, A., Lopez-Torres, M., Gustavo, B., 2001). This produces less
energy for the body and therefore less opportunity to repair itself, reduce cardiotoxicity, or
fight cancer.
Toxic Effects of Cancer Treatment
Because cancer is such an invasive and hard to treat disease, many times, the drugs
used to combat it have to be just as deadly, and may end in death. In some cases, the better
the drug works against cancer, the more fatal side effects it has. Some of the drugs used in
chemotherapy, specifically the anthracyclines, often cause cardiotoxicity in the heart
(Šimùnek, T, et al, 2009; Singal, P., & Iliskovic, N. 1998; Szuławska, A, & Czyż, M.,
2006). There are four different types of cardiotoxicity caused by anthracyclines. Acute
cardio toxicity occurs during or immediately after treatment is made involves
vasodilatation, hypotension and transient cardiac rhythm disturbances. (Šimùnek, et al,
2009). Subchronic cardio toxicity is uncommon and was mostly only observed where
larger doses of anthracyclines were used (Šimùnek, et al, 2009). This occurs 1-3 days
after treatment. Early chronic cardio toxicity occurs anywhere from a few days to weeks
after treatment. (Šimùnek, et al, 2009). It is characterized by “dilated cardiomyopathy,
with subsequent development of left ventricular contractile dysfunction and congestive
heart failure (CHF)”. (Šimùnek, et al, 2009, p. 156). Delayed cardio toxicity can occur
months, years, or even decades after treatment and usually, those with this type of
cardiotoxicity have a bad prognosis. (Šimùnek, et al, 2009). However, within these

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types of cardiotoxicities there are ways to combat the side effects and reduce the
cardiotoxicity itself. One such way is by using dexrazoxane.
Dexrazoxane is a drug that can reduce the amount of cardiotoxicity buildup in the
heart while preserving anthracyclines’ antitumor abilities (Hasinoff, B, & Herman, E.
2007). It works by binding to free iron in the heart, which is thought to reduce the amount
of reactive oxygen species that would be able to cause damage, therefore reducing overall
cardiotoxicity in the heart for the drug Doxorubicin specifically (Hasinoff, B, & Herman,
E., 2007). However, dexrazoxane is also a topoisomerase 2 inhibitor, which can cut
cancerous DNA and inhibit the process of it binding back together, effectively inducing
apoptosis in many cancer cells (Hasinoff, B, & Herman, E. 2007). Due to these
conflicting abilities, it is not fully understood how the two mechanisms work together
(Hasinoff, B, & Herman, E. 2007).
Fig. 2. Schematic overview of the pathways proposed to explain chronic anthracycline-induced cardiotoxicity. ANT –
anthracycline, FADD –Fas-associated death domain protein, iNOS – inducible nitric oxide synthase, MMP – matrix
metalloproteinase, MnSOD – manganese (mitochondrial) superoxide dismutase, mPTP – mitochondrial permeability transition
pore, PS – phosphatidylserine, ROS – reactive oxygen species, RNS – reactive nitrogen species, NO – nitric oxide, RyR
– ryanodine receptor, SR – sarcoplasmic reticulum, TnT/I – troponin T/I
Picture taken from pg 158; Šimùnek,T, Štìrba,M., Popelová,O., Adamcová, M., Hrdina, R., Geršl, V.
Anthracycline-induced cardiotoxicity:Overview of studies examining the roles of oxidative stress and free

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cellulariron. Pharmacological Reports. 2009;61, 154–171
The mechanisms bywhich manybiologicaland chemicals processes work are often
very elusive. One such puzzling process is calorie restriction (CR); a mechanism by which
researchers are endeavoring to reduce cardiotoxicity from chemotherapy drugs,
specifically doxorubicin. This is cutting edge research, as not many studies have been
conducted relating CR to cancer and sucheffects of the combination, althoughCR has been
shown to increase longevity. (Hursting, S., et al, 2003). Calorie restriction works by
reducing the amount of lipid peroxidation and other breakdown of materials and
molecules, where the overall free radical and reactive oxygen species count is reduced
(Koubova, J., & Guarente, L., 2003). Also, because of this reduced ROS production, less
malondialdehyde is produced. MDA is a type of TBAR, which is a ThioBarbituric Acid
Reactive Substance, a substance formed by lipid peroxidation that can become very
harmful to the body (Kosugi, H., Kojima, T., & Kikugawa, K., n.d.) These create DNA
adducts, which are pieces of DNA that are covalently bonded to a chemical in an unnatural
way, specifically those that are cancer causing (Kosugi, H., et al, n.d.). This binding action
creates a pigment which can then be quantitatively analyzed for damage via a
spectrophotometer (Kosugi, H., et al, n.d.). Calorie restriction does reduce the amount of
oxidative stress and damage to tissues, but by what mechanism is unknown, although it is
known to increase longevity and reduce age-related diseases (Minor, et al, 2010; Hursting,
S., et al, 2003; Helibronn, L, & Ravussin, E., 2003). In addition, because less energy is
being produced by mitochondria, the same effect occurs (ATP production produces free
radicals).
Other longevity-promoting interventions sometimes work by creating more

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reactive oxygen species which in turn switch on defense mechanisms inside the cell,
increasing oxidative stress resistance and longevity over time. (Ristow & Schmeisser,
2010). In fact, by taking in antioxidants and partially inhibiting such processes, this might
result in an adverse effect by decreasing stress resistance otherwise obtained through
calorie restriction and exercise. (Ristow & Schmeisser, 2010). Although antioxidants may
decrease levels of harmful free radical species that can damage cells in different types of
tissue, absorbing too many of them may decrease one’s resistance to possible future
oxidative stress (Ristow & Schmeisser, 2010). Therefore, both reducing and increasing the
amount of ROS and oxidative stress in cells can be both beneficial and harmful. However,
it is shown that ROS production and oxidative stress are not large contributors to antitumor
activity. (Šimùnek, et al, 2009).
Alternative Cancer Treatments
As cancer rates continue and escalate, there is an increasing demand for alternative,
cost effective ways of treating cancer. These alternative methods can include exercise,
medicinal/herbal supplements, acupuncture, hypnosis, biofeedback, etc. Manyof these just
alleviate side-effects, not necessarily kill cancer cells (Types of Treatment, National
Cancer Institute). Calorie restriction may become one of the new and one of the most
effective types of alternative cancer treatment.
Few studies have been done specifically pertaining to calorie restriction and its
effects on cancer or cancer therapy. One such study that has been done is that of
mitochondrial free radical generation pertaining to calorie restriction for mitochondrial
DNA in rat hearts (Gredilla, R., et al, 2001). It was shown that by calorie restricting rats,
H2O2 generation (a harmful chemical when inside the body) is decreased and reduces the

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amount of damage done to DNA and cells in general. (Gredilla, R., et al, 2001). It was
shown that short term calorie restriction (6 months) did not procure any differences in free
radical production, but in long term calorie restriction (1 year or more), less free radicals
were produced from the mitochondria in heart cells. (Gredilla, R, et al, 2001). Therefore,
by calorie restricting an organism, less free radicals and reactive oxygen species are
produced from energy production in mitochondria, less damage is incurred, and heart cells
are then healthier, which can then help to predispose an organism to have a better cancer
treatment outcome (Gredilla, R., et al, 2001). Also, there have been studies done showing
that CR can reduce the amount and severity of brain tumors in mice (Shelton, L., et al,
2010). This is because calorie restriction reduces the amount of circulating glucose in the
body, which then prevents tumors from growing more rapidly due to an availability of an
energy source (Shelton, L., et al, 2010). Because of these promising studies pertaining to
calorie restriction, more are being done in an attempt to find a new and effective cancer
treatment.
Methods and Materials
Animal Care
Ten week old female Sprauge-Dawley rats were obtained from Harlan
Laboratories, Indianapolis, Indiana. All animals were housed in a temperature controlled
facility, provided water ad libitum, and were adapted to a 12 hour light : 12 hour dark cycle.
All proposed protocols were approved bythe Universityof NorthernColorado Institutional
Animal Care and Use Committee and were in compliance with the Animal Welfare Act
guidelines.

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Calorie Restriction Protocol
Nine week old female Sprauge-Dawley rats were fed ad libitum (provided 600 g)
for a week with standard rat chow to calculate and average consumption rate. During week
1 ofthe experiment (rats 10 weeks old) and in the following10 weeks, the calorie restricted
group (experimental group) was provided 60% of average consumption each week (new
averages at end of every week). Both of the groups (ad libitum and calorie restricted) were
sedentary and provided water ad libitum. At the end of the 10 week experimentation
period, free fed or calorie restricted rats were injected with doxorubicin or saline (control),
and euthanized and dissected for analysis.
Tissue Preparation
Left ventricles of Sprauge-Dawley rat hearts were dissected, obtained and flash
frozen in liquid nitrogen. 250 milligrams of ventricle tissue for each sample were weighed
and minced into small pieces with scissors. Minced tissue was inserted in to a glass test
tube; 1 mL/250 mg of tissue of RIPA (Sigma Aldrich, St. Louis, MO.) buffer was added.
Tissue and buffer mix was homogenized in the test tube with a glass tissue grinder.
Samples were then centrifuged at 10,000 g for 10 minutes and supernatant was decanted.
10 μL of supernatant was extracted and ejected into 1.5 mL cuvettes for every sample. A
standard curve was obtained from protein standards at 0, .125, .25, .5, 1, and 2 ng/ml,
(using spectrophotometer). 1 mLof Bradford Reagent (Sigma Aldrich, St. Louis, Mo.) was
added to cuvette and incubated for 5 minutes. Absorbency was measured via a
spectrophotometer at 595 nm to determine total protein content. Process was repeated for
all samples.

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Myocardial lipid peroxidation
The following tissue preparation was done using a commercially available kit,
Bioxytech MDA-586, Spectrophotometric Assay for Malondialdehyde (Oxis
International, Portland, Ore.). 10 μL of probucol was added to new test tubes. 200 μL of
sample was added to respective assay tubes as well as 640 μL of diluted R1 reagent. All
samples were then mixed bybriefly vortexing each tube. 150 μLof R2 was added to all test
tubes and then stoppered in order to mix well by vortexing for approximately 30 seconds.
Test tubes were then incubated at 45 degrees Celsius for 60 minutes. Turbid samples were
then centrifuged (10 minutes at 11 rpm) to obtain a clear supernatant. 200 μL of clear
supernatant was transferred to respective cuvettes. Absorbency of each sample was
measured at 586 nm.
Statistical Analysis
A one-way ANOVA test was utilized to determine any significant statistical
differences between the four experimental groups. (p<0.05)
Results
No significant data was found between the 4 experimental groups; the p-value of
the data was shown to be greater than .05. It was shown that the CR_SAL (calorie
restricted, saline injected) experimental group did have an overall less amount of MDA in
heart tissue (the average being 5.17 μM) compared to AL_SAL (ad libitum, saline injected)
and AL_DOX (ad libitum, doxorubicin injected) experimental groups amounts of MDA in
heart tissue (averages being 6.8 μM and 6.3 μM respectively). The data demonstrates that
calorie restrictiondoes reduce the amount ofMDA in heart tissue overall, therefore making
the heart more healthy and accumulating less damage. The total protein content part of the

15
experiment was a success, showing that the total protein within each of the samples was at
the same average. Because the experiment had a small sample size and the mortality of the
DOX injected rats was moderate, the results may be skewed.
Figures
Treatment
Group
(n=
) MDA MeanS.D.
CR+SAL 5 5.175610 .887
CR+DOX 8 6.036585 .978
AL+SAL 7 6.808362 .631
AL+DOX 8 6.344512 .630
Table 1. Mean ± standard deviation (S.D.) of each treatment group for malondialdehyde
(MDA) concentrations.
Figure 1. Graph of mean malondialdehyde(MDA) content in µM
among treatment groups. CR_SAL, Calorierestricted + saline
injection;CR_DOX, calorierestriction +doxorubicin injection,AL_DOX,
Ad Libitum + doxorubicin injection,AL_SAL, Ad Libitum+ saline
injection.Significancewas found between CR_SAL and AL_DOX. *
indicates significanceto a p<.05

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Discussion
Although no significant results were found, the experiment is the precursor to
future, more effective and significant experiments. This experiment did show that calorie
restriction does in fact reduce amounts of harmful MDA levels in left ventricle cardiac
tissue of Sprauge-Dawley rats. The experimental group with the highest level of MDA
accumulation in heart tissue was the ad libitum, doxorubicin injected rats, naturally. These
rats experienced more lipid peroxidation and side effects of doxorubicin, therefore more
free radical species produced and more damage done.
The second highest level of MDA found was in ad libitum, saline injected rats,
which would be the normal case due to the neutral effects of saline and the increased ROS
production from more calorie intake. The next highest MDA level groups were in calorie
Figure 2. Total protein contents of the separateexperimental
groups, showingthat the total protein content of left ventricles
were similar (control) (mgof protein/mL tissuehomogenate).
P>.05

17
restricted, doxorubicin injected rats and then in calorie restricted, saline injected rats,
respectively. These results are expected, and because of this normalcy, the experiment was
a success. However, the results did not support the hypothesis proposed because no large
enough difference in MDA content was found between the four experimental groups.
However, the future experiments of the same nature may prove to show significant data
due to larger sample size.
Cancer is an extensive and consequential disease that affects thousands of people
worldwide. It can be considered as one of the predominant demises of medical system
because of its pervasive and devastating nature. Many researchers exploringpotential cures
for this plague of a disease, and any progress in this field is remarkable. Even though the
study may have not shown significant results pertaining to the experiment, showing what
doesn’t work may be just as effective as the prior, although the study did not show
confirmation of success or no success at all.
The calorie restriction was shown to reduce MDA levels, however, not shown to
help in cardiotoxicity explicitly. This does not mean that on a larger scale, CR couldn’t
help in reducing cardiotoxicity levels in heart tissue. The experiment does show potential
for possible progression and significant findings because it does not refute the hypothesis
nor support it. As the study advances and the sample size become larger, hopefully more
significant data becomes apparent.
If the conglomerated data from multiple experiments does support that calorie
restriction helps in reducing cardiotoxicity levels in the heart, the possibilities are
amaranthine. Calorie restriction is just one of the ways to reduce numbers of ROS inside
the body, and can possibly reduce cardiotoxicity. As of now there are other known

18
techniques to reduce cardiotoxicity such as exercise. Exercise has been shown to reduce
cardiotoxicity by inhibiting apoptotic signaling and providing resistance against oxidative
stress (Chicco, A., Hydock, D., et al, 2005; Chicco, A., Schneider, C., et al, 2005).
Antioxidant supplements, however, have not been shown to significantly reduce
cardiotoxicity in the heart, even though supplements are commonly used as alternative
treatment for chemotherapy patients (Block, K., et al, 2008). However, specifically for
doxorubicin treatment, antioxidant supplements do help via antioxidant activity against
free radicals and ROS produced at the electron transport chain malfunction (Oliveiraa, P.,
et al, 2004). Adding calorie restriction to other known interventions such as exercise may
increase the beneficial effects and increase chemotherapy survivorship.
Conclusion
Cancer is a widespread and often fatal disease of which many are working to
alleviate. Novel and diverse experiments are being conducted in order to attempt to find a
cure for this disease or even just help to reduce the side effects of treatment or cancer itself.
Calorie restriction might prove to be one of these new treatments in the near future.
Although our experiment did not come up with significant data, when a larger sample size
is obtained, it may show that calorie restriction does help reduce doxorubicin-induced
cardiotoxicity in heart tissue. If this is true, survivorship of patients may increase and in
conjunction with other treatments, cardiotoxicity from chemotherapy may be reduced to a
negligible amount. In the future, cancer treatments may become so effective that the
disease may become something of the past, and researchers will be able to continue onto
other investigations within modern medicine.

19
Acknowledgements
There are several people whom we would like to thank, as this project would not
have come this far without them. The first is Lori Ball, the coordinator of FSI, who made it
possible for us to participate in this experiment, and has helped guide our papers the whole
way through. We would also like to thank Nathan Kirkley and Klaus Broeker for editing
our papers and giving us suggestions on how to make them more appealing. Next, we
would like to thank University of Northern Colorado for letting us use their facilities and
also for the FSI program for allowing us to participate in all of our activities. Also, we
would like to thank all of the teachers and RA’s for helping us along in the program and
teaching us new and interesting information; Abby Davidson, Nick True, Zabedah Saad,
Nathan Kirkley, Kayla Schinke, Klaus Broeker, and Karen Allnutt. Lastly, we would like to
thank our mentor, Noah Gibson and Dr. Reid Hayward, for giving us the opportunity to
work on this novel research. We would also like to thank our sponsors who made it possible
for us to be in the FSI program this year and for helping to fund our research; Adolph
Coors Foundation, Bacon Family Foundation,, The Edward Madigan Foundation, and FSI
alumni.

20
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