Carbon Monoxide Prevents Growth in Prostate, Lung
Tumors; Enhances Chemotherapy
Opens possibility of new cancer therapy to take
advantage of powerful chemotherapy drugs making them more potent and
limiting terrible side effects, damage to normal cells
Dec. 4, 2013 It is hard to imagine anything good
coming from carbon monoxide, the highly toxic gas the shoots out your
auto exhaust, but a new study says it can play a role in treating
cancer. It can prevent tumor growth in prostate and lung cancers and can
amplify the effectiveness of chemotherapy 1,000-fold while sparing
noncancerous tissue from chemo's sometimes debilitating side effects.
The surprising new findings, described in the
December issue of the journal Cancer Research, show that in cell
culture and animal models carbon monoxide (CO) can be effective.
Previous research has suggested CO can also be used to treat certain
inflammatory medical conditions.
The new study led by a research team at Beth Israel
Deaconess Medical Center (BIDMC) shows for the first time that carbon
monoxide appears have potential in successfully treating cancer.
"We found that in small, carefully controlled
doses, CO not only mimicked the effects of chemotherapy agents by
blocking proliferation of cancer cells, but also amplified the toxic
effects of the chemotherapy drugs doxorubicin and camptothecin to
accelerate cancer cell death," says senior author Leo Otterbein, PhD, an
investigator in the Transplant Institute in BIDMC's Department of
Surgery and Associate Professor of Surgery at Harvard Medical School.
"Importantly and rather unique is that CO also
helped to protect normal tissue from chemotherapy, which is an
unfortunate side effect of the treatments."
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The new discovery appears to hinge on CO's ability
to switch the metabolic state of cancer cells so that tumors essentially
work themselves to death.
"There are fundamental differences in the
metabolism of normal cells and cancer cells," explains Otterbein.
"Cancer cells are able to alter their metabolism in processing sugars
and other energy sources, which enable them to rapidly proliferate and
spread. This shift in metabolism is known as the Warburg Effect. Our
findings indicate that CO essentially induces an 'anti-Warburg' effect,
rapidly fueling cancer cell bioenergetics by compelling the cancer cell
to increase respiration, which ultimately results in metabolic
The body naturally generates CO under stress
through the increased expression of the gene heme oxygenase-1 (HO-1
Hmox1), a cytoprotective stress response gene that generates CO as it
catabolizes heme, an essential component of many proteins such as
The increase in HO-1 has been shown to occur under
numerous and diverse stressors, such as inflammation, trauma and even
Tumors, however, are often absent this capability
because HO has become inactive and unable to generate sufficient levels
of CO. In this new paper, Otterbein and first author Barbara Wegiel,
PhD, also an investigator in BIDMC's Transplant Institute, wanted to
find out if a tumor's inability to produce CO naturally was what was
fueling cancer growth.
"If A plus B equals C, then, we reasoned, if you
administered carbon monoxide to tumors, you would reestablish a tumor
cell's ability to regulate its cell growth, and so, too, slow that
growth," says Otterbein.
The authors first conducted a detailed analysis of
more than 500 tumor samples from prostate cancer patients. "Through
these biopsies, we confirmed expression of HO-1," explains Wegiel, who
is also an Assistant Professor of Surgery at HMS. "But we found that
HO-1 in the tumor was simply not active. It was not producing sufficient
amounts of CO, and we thought this was contributing to altered cell
growth and malignancy."
This finding led to their hypothesis that HO-1,
through its ability to generate CO, was regulating the growth of cancer
cells, a discovery that had been observed and well described in other
cell types. To test this hypothesis, mice with established tumors were
started on a regimen of inhaled CO of one hour per day at a safe, low
concentration, equal to that approved for use in humans in ongoing
Tumor size was measured daily over four to six
weeks. In the cancer cell CULTURES, metabolic activity in the
mitochondria the cells' energy-generating organelle - were measured
using biochemical markers as well as imaging techniques.
"We found that exposure to CO sensitized the
prostate cancer cells - but not the normal cells - to chemotherapy,"
explains Otterbein. "CO targeted mitochondria activity in cancer cells
as evidenced by higher oxygen consumption, free radical generation and,
ultimately, mitochondrial collapse.
"Collectively, our findings indicated that CO
induces an anti-Warburg effect by rapidly fueling cancer cell
bioenergetics, ultimately resulting in metabolic exhaustion," he adds.
Importantly, CO protected normal cells from DNA damage generated by
cytotoxic agents, in part by reducing oxygen consumption and eliciting a
hibernation-like state in these cells.
"Essentially, these normal cells entered growth
arrest and slowed their metabolic rate, in marked contrast to the cancer
cells, which continued to consume oxygen at a rate that ultimately led
to their demise," Otterbein said.
While the authors note that more research will be
needed to confirm these findings, they provide a promising new direction
for cancer treatment.
"Chemotherapy remains the first-line therapy for
many types of cancer, including breast and lung cancers," notes study
coauthor and BIDMC Chief Academic Officer Vikas Sukhatme, MD, PhD.
"But chemotherapy's debilitating side effects and
limited effectiveness are well known. This new finding opens up the
possibility of new therapeutic interventions that take advantage of
powerful chemotherapy drugs, perhaps making them even more potent while
simultaneously limiting their terrible side effects and damage to normal
cells and tissues.
There are ongoing innovative methodologies being
designed and tested to deliver CO directly to the tumor site, which
might obviate the need for additional drugs. Indeed, small molecules are
being designed that can carry CO as a cargo and deliver it in a
This work was supported by grants from the National
Institutes of Health (HL-071797; HL-076167, as well as support from AHA,
the Julie Henry Fund, the British Heart Foundation and Medical Research
In addition to Otterbein, Wegiel and Sukhatme,
study coauthors include BIDMC investigators David Gallo, Eva Csizmadia,
Clair Harris, Pankaj Seth and Pier Paolo Pandolfi and investigators John
Belcher, Gregory Vercellotti, Leszek Helczynski, Anders Bjartell, Jenny
Liao Persson, Nuno Penacho and Asif Ahmed.
Beth Israel Deaconess Medical Center is a patient
care, teaching and research affiliate of Harvard Medical School and
currently ranks third in National Institutes of Health funding among
independent hospitals nationwide.
BIDMC has a network of community partners that
includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess
Hospital-Needham, Anna Jaques Hospital, Cambridge Health Alliance,
Lawrence General Hospital, Signature Health Care, Commonwealth
Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care
Alliance, and Atrius Health. BIDMC is also clinically affiliated with
the Joslin Diabetes Center and Hebrew Senior Life and is a research
partner of the Dana-Farber/Harvard Cancer Center. BIDMC is the official
hospital of the Boston Red Sox. For more information, visit
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