Lonidamine: basic science and rationale for treatment of prostatic proliferative disorders

Abstract

Normal and hyperplastic prostatic tissues concentrate citrate within the epithelium; however, a unique biochemical property within prostate epithelial cells renders them dependent on glycolysis, rather than the citric acid cycle, for energy production. Lonidamine, an orally administered small molecule that inhibits glycolysis by the inactivation of hexokinase, may represent a unique and novel approach to the treatment of benign prostatic hyperplasia (BPH). Results of a phase II trial of lonidamine in BPH (described elsewhere in this supplement) are encouraging. Lonidamine is already used in the treatment of several cancers in other countries. Its target-specific nature renders it a safe compound for administration; in cancer therapy, patients have been treated with 40 times the daily dose used in the BPH trial, with negligible toxicity.

Figure 1

α-Blockers and 5α-reductase inhibitors are highly effective for managing the symptoms of BPH but do nothing to permanently halt or reverse the hyperplastic process. An ideal agent would tip the balance to increase apoptosis and decrease proliferation of prostatic cells. BPH, benign prostatic hyperplasia.

Figure 2

Lonidamine, a derivative of indazole-3-carboxylic acid, is an orally administered small molecule that inhibits glycolysis by the inactivation of hexokinase, and is used as a cancer therapy in a number of countries. Originally used as an antispermatogenic agent, it is currently being investigated for use in treating benign prostatic hyperplasia.

Figure 3

Hexokinase, an enzyme that catalyzes glucose as the first step in glycolysis, is inhibited by lonidamine. ADP, adenosine diphosphate; ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide (reduced form).

Figure 4

A single 100 mg/kg dose of a lonidamine analogue led to a 24% reduction in prostate weight in the Long-Evans rat model. Data from Lobl et al.

Figure 5

Caspase-3 (Casp3) activity and lonidamine (LND) in the prostate LNCaP cell line, stroma, and mammary cells.