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J Cancer Metastasis Treat 2020;6:5 I http://dx.doi.org/10.20517/2394-4722.2020.13 Page 37 of 38

51. Cancer chemoprevention with mitochondria-targeted compounds

Ming You

Center for Disease Prevention Research and Department of Pharmacology and Toxicology, Medical College of
Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.

We synthesized two mitochondria-targeted compounds, namely mito-honokiol (Mito-HNK) and mito-
lonidamine (Mito-LND), that facilitate their mitochondrial accumulation. This dramatically increases their
potency and efficacy against highly metastatic lung cancer lines in vitro, orthotopic lung tumor xenografts,
and brain metastases in vivo. Both Mito-HNK and Mito-LND are > 100-fold more potent than their parent
compounds in inhibiting cell proliferation and mitochondrial complexes, stimulating reactive oxygen
species generation, and oxidizing mitochondrial peroxiredoxin-3. Interestingly, Mito-HNK appears to
induce apoptosis via suppressing the phosphorylation of mitoSTAT3, while Mito-LND induces autophagic
cell death via inactivating AKT/mTOR/p70S6K signaling. Both Mito-HNK and Mito-LND cause no
toxicity in mice, even when administered for eight weeks at > 20 times the effective cancer inhibitory dose.
A highly synergistic effect is observed when combining the two compounds and its mechanistic basis is
being vigorously pursued. Collectively, these findings show that mitochondrial targeting compounds are a
promising preventive/therapeutic approach to mitigate lung cancer development and brain metastasis.

52. The efficacy of ketogenic diet with concomitant intranasal perillyl alcohol as a novel
strategy for therapy of recurrent glioblastoma

Juliana G. Santos1, Wanise S. Cruz1, Axel H. Schönthal2, Thereza Q. Santos3, Clovis O. Da
Fonseca4

1 Department of Nutrition, Fluminense Federal University, Niteroi Rio de Janeiro 24220-900, Brazil.
2 Keck School of Medicine, University of Southern California, Los Angeles, CA 90007, USA.
3 Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi Rio
de Janeiro 24220-900, Brazil.
4 Service of Neurosurgery, Fluminense Federal University, Niteroi Rio de Janeiro 24220-900, Brazil.

Background: It has been hypothesized that persistent ketotic hypoglycemia might represent a potential
therapeutic strategy against high-grade gliomas. Perillyl alcohol (POH) is a non-toxic, naturally-occurring,
hydroxylated monoterpene that exhibits cytotoxicity against temozolomide-resistant glioma cells, regardless
of O6-methylguanine-methyltransferase promoter methylation status. This study aimed to evaluate the
toxicity and therapeutic efficacy of intranasal POH administered in combination with a ketogenic diet (KD)
program for the treatment of patients with recurrent glioblastoma.

Patients and methods: Thirty-two patients were divided into two groups - KD or standard diet - both
associated with intranasal POH (n = 17 and n = 15, respectively). The nutritional status and anthropometric
parameters of patients were measured. Patients who adhered to the KD maintained a strict dietary regimen,
while receiving inhalation of POH (55 mg, four times daily) in an uninterrupted administration schedule
for three months. Neurological examination and imaging analysis (magnetic resonance imaging) were
used to monitor disease progression. Clinical toxicity and overall survival were correlated with tumor size,
topography, extent of peritumoral edema, and frequency of seizures. In the KD patient, strict compliance
with the KD was confirmed by measuring the levels of ketone bodies in the urine (9/17 patients) three
times per week.