3.4

Drug Repositioning Intended for Anticancer Applications

3.4.1

Itraconazole

Itraconazole was developed in 1980s as a triazole antifungal drug and was effective

against a variety of systemic fungal infections like other members of the azole family

of antifungal drugs. The well-established mechanism of antifungal activity of

itraconazole involves the inhibition of cytochrome P450-dependent lanosterol

14-α-demethylation (14DM) in pathway associated with ergosterol biosynthesis in

fungi (Vanden Bossche et al., 1988). Antiangiogenic property of itraconazole leads

to its usage either alone or in combination with other anticancer drugs in various

preclinical models, including medulloblastoma, non-small cell lung cancer

(NSCLC), and basal cell carcinoma (Kim et al., 2010; Aftab et al., 2011; Tsubamoto

et al., 2017).

3.4.2

Digoxin

Digoxin, a cardiac glycoside isolated from foxglove, has been historically used for

treating heart failure and arrhythmia (Hollman, 1996). Digoxin is a potent inhibitor

of Na+/K+-ATPase pump in cell membrane (Rossi et al., 1982). The regulation of

sodium ion gradient across the cell membrane by Na+/K+-ATPase leads to intracel-

lular Ca²⁺ ion efflux. The increase in intracellular Ca²⁺ concentration in

myocardiocytes and pacemaker cells, resulting in lengthening of the cardiac action

potential, is associated with the inhibition of Na+/K+-ATPase by digoxin

(Belardinelli et al., 1979). It was later demonstrated that this cardiac glycoside

triggered immunogenic demise of the cancer cells (Kepp et al., 2012).

3.4.3

Nitroxoline

Nitroxoline, an antibiotic which has been widely used almost throughout the world

since 1960s, is specifically used in the treatment of urinary tract infections (UTI) due

to its unique pharmacokinetic property. Oral administration of nitroxoline leads to

rapid absorption into the plasma followed by excretion via urine (Mrhar et al., 1979).

The long retention time of nitroxoline in urine makes it an ideal candidate for UTI

treatment. The mechanism of action of nitroxoline works on its ability to chelate

divalent metal ions, such as Mg²⁺ and Mn²⁺, resulting in its possible antibacterial

activity (Pelletier et al., 1995). Recently, the anticancer activity of this antibiotic has

been demonstrated in prostate cancer (Chang et al., 2015).

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Drug Repurposing in Biomedical Research: Benefits and Challenges

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