Efficacy of a ketogenic diet with concomitant intranasal perillyl alcohol as a novel strategy for the therapy of recurrent glioblastoma

Abstract

Abstract. It has been hypothesized that persistent ketotic hypoglycemia represents 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. The present study aimed to evaluate the toxicity and therapeutic efficacy of intranasal POH when administered in combination with a ketogenic diet (KD) program for the treatment of patients with recurrent glioblastoma. The 32 enrolled patients were divided into two groups, KD or standard diet, with intranasal POH treatment (n=17 and n=15, respectively). The nutritional status and anthropometric parameters of the patients were measured. Patients that adhered to the KD maintained a strict dietary regimen, in addition to receiving 55 mg POH four times daily, in an uninterrupted administration schedule for three months. Neurological examination and magnetic resonance imaging analysis were used to monitor disease progression. A total of 9/17 patients in the KD group survived and maintained compliance with the KD. After three months of well-tolerated treatment, a partial response (PR) was observed for 77.8% (7/9) of the patients, stable disease (SD) in 11.1% (1/9) and 11.1% (1/9) presented with progressive disease (PD). Among the patients assigned to the standard diet group, the PR rate was 25% (2/8 patients), SD 25% (2/8) and PD 50% (4/8 patients). The patients assigned to the KD group presented with reduced serum lipid levels and decreased low-density lipoprotein cholesterol levels. These results are encouraging and suggest that KD associated with intranasal POH may represent a viable option as an adjunct therapy for recurrent GBM.

Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats

“…However, perillic acid, the primary metabolite of POH, was easily measurable during PK studies of oral POH in cancer patients, and was shown to reach peak levels (C max ) of 600-770 μM. 7,8,11,12 Our current study is focused on pharmacology of POH and, most importantly, the introduction of a novel method that allows the simultaneous detection and measurement of POH and perillic acid. 5,31,32 Importantly, in the present work a methodology of HPLC-UV chromatography was developed and applied, which simultaneously determined the presence of POH and its metabolite PA in Wistar rats after inhalation of POH.…”

“…A similar outcome was reported by Xu et al 6 after POH treatment of H322 and H838 lung cancer cell lines. 9,10 As an alternative to oral dosing, two clinical studies in Brazil 11,12 pioneered inhalational administration of POH and demonstrated that this approach was feasible and very well tolerated. 7,8 However, clinical trials with oral dosing of POH were disappointing, because the large number of capsules (gram quantities) that had to be swallowed 3-4 times a day on a continuous basis caused unrelenting grade 1 and grade 2 gastrointestinal (GI) effects and fatigue, which proved to be limiting.…”

“…In fact, the unremitting nature of these side effects resulted in several subjects declining further participation in these trials. 9,10 As an alternative to oral dosing, two clinical studies in Brazil 11,12 pioneered inhalational administration of POH and demonstrated that this approach was feasible and very well tolerated. In patients with recurrent gliomas, inhalation of POH through the nose (intranasal delivery) resulted in promising anticancer activity.…”

Evaluation of phytomedicinal potential of perillyl alcohol in an in vitro Parkinson's Disease model

“…PA also has the advantage of being a treatment agent of herbal origin which is generally conceived as being safe by the general populace and has minimal side effects as compared to conventional drugs used in PD therapy. In recent times, PA has been used to treat a variety of disorders (Rodriguez, Carvalho, Kimura, & Katzin, ; Santos et al, ), but there are no reports of it being utilized in a PD model system yet.…”

“…In recent times, PA has been used to treat a variety of disorders (Rodriguez, Carvalho, Kimura, & Katzin, 2018;Santos et al, 2018), but there are no reports of it being utilized in a PD model system yet.…”