Activity

A lipoxygenase inhibitor in breast cancer
brain metastases
D. F. Flavin1
(1) Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich,
CT 06831, USA
D. F. Flavin
Email: Dana_FK@hotmail.com
Phone: +1-203-6610911
Received: 23 July 2006 Accepted: 11 August 2006 Published online: 26 September 2006
Abstract The complication of multiple brain metastases in breast cancer patients is a life
threatening condition with limited success following standard therapies. The arachidonate
lipoxygenase pathway appears to play a role in brain tumor growth as well as inhibition
of apoptosis in in-vitro studies. The down regulation of these arachidonate lipoxygenase
growth stimulating products therefore appeared to be a worthwile consideration for
testing in brain metastases not responding to standard therapy. Boswellia serrata, a
lipoxygenase inhibitor was applied for this inhibition. Multiple brain metastases were
successfully reversed using this method in a breast cancer patient who had not shown
improvement after standard therapy. The results suggest a potential new area of therapy
for breast cancer patients with brain metastases that may be useful as an adjuvant to our
standard therapy.
Keywords Cancer – Lipoxygenase – Boswellia serrata – Oxidoreductase inhibitor –
LOX inhibitors – Lipoxygenase inhibitor – Brain Cancer – Breast Cancer – Metastases –
Breast Cancer Remission – Arachidonate: Oxygen oxidoreductase – Herceptin
A 39-year-old woman presented with symptoms of headache and nausea to her physician.
She had been operated on 1 year earlier for primary breast cancer, stage I, with no
metastases or lymph node involvement, followed by a monotherapy study with
trastuzamab because of her tumor’s HER2 positive receptors. Following a negative
physical examination further staging included a tumor marker evaluation and a computed
tomography (CT) scan for her head. The results showed multiple brain metastases
(Fig. 1a, b).
Fig. 1 CT before Boswellia
The patient was started on capecitabine and given radiation therapy of 44 Gy with no
improvement seen for the first 2 weeks. The severity and inoperability of her condition
made using an additional therapy a consideration. An oxidoreductase [plant
lipoxygenases (LOX)] inhibitor was applied (Boswellia serrata) which has no known
major side effects. The enzyme, LOX, arachidonate: oxygen oxidoreductase (form
mammalian LOX) is thought to be responsible for edema in primary brain tumors and
present ongoing studies on LOX inhibitors in Germany indicate an overall improvement
in response to radiation therapy as well as a decrease in some primary brain tumors seen
even without radiation. Although it was not known if LOX inhibitors would be helpful in
breast cancer brain metastases it was worth considering in this case since she had not
only several large tumors but also additional extremely small tumors scattered throughout
the brain. She was immediately placed on a LOX inhibitor. Following 10 weeks of
therapy, the patient was scheduled for a new CT since her CEA and Ca 15–3 tumor
markers had increased. The CT results showed a complete disappearance of all signs of
metastases in her brain (Fig. 2a, b).
Fig. 2 CT after Boswellia (10 weeks)
The patient has been maintained on the LOX inhibitor, Boswellia serrata, 3 × 800 mg/day
with no new signs of cerebral involvement of her breast cancer for over 4 years, however,
there have recently been skeletal metastases which most likely indicates LOX has a
limited skeletal tissue involvement in cancer.
Since life expectancy decreases to 3–5 months with multiple brain metastases its
appearance is a dreaded complication in breast cancer patients. The incidences of central
nervous system (CNS) metastases following breast cancer treatments with trastuzumab
are 25–34%. This is an unfortunate complication thought to be a result of the inability of
trastuzumab to cross the blood brain barrier in HER2 positive patients [1]. Brain
metastases are often treated with surgical resection, stereotactic radiosurgery, whole brain
radiation therapy or chemotherapy [2–4]. Even though combination therapies are often
applied the survival rate for multiple brain metastases is still very poor [5], and even
though usually not very successful, some benefits have been seen with the use of
chemotherapy in individual cases [6].
The metabolites of the LOX hydroxyeicosatetraenoic acid (HETE) derivatives in the
arachidonic acid (AA) cascade have been shown to inhibit apoptosis, programmed cell
death. Inhibition of LOX has proven to be effective in inducing apoptosis. The
mechanisms of the LOX inhibitors to promote apoptosis is by decreasing the
antiapoptotic gene, bcl-2 [7], and by decreasing the antiapoptotic phosphatidylinisitol-3
(PI-3) kinase-Akt signaling pathway [8]. Furthermore, a link has been shown between the
activity of the tumor-suppressor gene p53 and 15 LOX (h15-LO). When the p53 is
mutated the h15-LO is increased causing tumor growth and preventing cell death [9].
Similarly in vascular smooth muscle cells LOX metabolites promote vascular cell growth
by stimulating cFos, cJun, and cMyc mRNA expression. Additionally linoleic acid
activates the ras gene further enhancing cell growth and replication [10].
After seeing the impact of LOX in cancer cell growth it should not be considered unusual
that LOX have been found to be elevated in human brain tumors, including meningeoma
and glioblastoma. Some of the LOX involved are thought to be present because of the
macrophage/monocyte infiltration [11]. Further research studies have indicated that LOX
also has a role in prostate cancer [12], pancreatic cancer [13], and breast cancer [14].
Most likely the entire AA cascade and the metabolites of AA and LOX are working
synergistically in promoting tumor growth and preventing apoptosis. The successful
regression and lengthy remission of this patient’s brain metastases would seem to indicate
that the LOX inhibitors were potentially responsible for staving off new CNS metastases
and perhaps, may prove fruitful in other cancers mentioned above.
Acknowledgements This work was supported by The Samuel Freeman Charitable Trust
and the M.J. and Caral G. Lebworth Foundation. Special Thanks to Dr. Albert Scheller
(deceased 9/’05) of the Leonardis Oncology Clinic in Bad Heilbrunn, Germany for his
excellent additional care of this patient, and Dr. Ursula Jacobs for her continued
assistance in therapy.
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