Alternol/Alteronol: Potent Anti-cancer Compounds With Multiple Mechanistic Actions

Abstract

Alternol and its oxidate isomer Alteronol are small compounds isolated from the fermentation of a mutant fungus obtained from Taxus brevifolia bark. Preclinical studies showed their potent anti-cancer activities, including attenuating cellular survival pathways, altering protein levels of cell cycle regulators, activating xanthine dehydrogenase to cause accumulation of cellular reactive oxygen species and disrupting cell metabolism by disturbing four Krebs cycle enzymes specifically in malignant cells while having no significant effect on benign cells. In cancer cell culture models, Alternol or Alteronol exert their anti-cancer effect by inducing cell cycle arrest and triggering apoptotic cell death. In mice xenograft models, Alternol or Alteronol potently suppresses tumor growth with no obvious toxicity to the host with a wide therapeutic index over 30-fold. In conclusion, Alternol or Alteronol possess a great potential and feasibility to be developed as an effective anti-tumor therapeutic.

Keywords: Alternol; Alteronol; Cladosporol; apoptosis; cell cycle; radical oxygen species.

FIGURE 1

Chemical structures for Alternol, Alteronol and Cladosporols. The differences between these two pairs of isomer compounds were highlighted in red-dotted circle, indicating the oxidate site in Alteronol and Cladosporol B.

FIGURE 2

Alternol/Alteronol induce cell cycle arrest in cancer cells by attenuating the expression of cell cycle regulators, including down-regulation of CDK2/4, Cyclin D1, PCNA, PLK1 and CDC25 expression and up-regulation of Wee1 and p21^cip1/waf1 expression.

FIGURE 3

Alternol and Alteronol induce ROS accumulation by activating cytosolic XDH, resulting in Bax activation, cytochrome c release and apoptosis. Alternol/Alteronol also reduces the expression of anti-apoptotic Bcl-2 and Survivin proteins but enhances the expression of pro-apoptotic p53 protein, leading to intrinsic apoptotic cell death. Pink dots denote activated Bax proteins and light-blue dots denote cytochrome c proteins.

FIGURE 4

The mechanisms of Alternol/Alteronol-induced anti-cancer effects. Alternol and Alteronol reduce cell proliferation via cell cycle arrest, trigger apoptotic cell death via ROS accumulation and AKT/mTOR inactivation and attenuate cell motility by down-regulating MMP-2/9 expression. Alternol enhances autophagy flux via AMPK activation/AKT-mTOR inactivation and causes energy crisis by inhibiting Krebs’ cycle enzymes PDH/DLAT and KGDH/DLST complexes. Blue solid arrows denote a direct stimulating effect. Red solid lines denote a direct suppressive effect. Red dotted lines denote an indirect suppressive effect. Abbreviations: AMPK, AMP-activated protein kinase; DLAT, dihydrolipoyllysine-residue acetyltransferase; DLST, dihydrolipoyllysine-residue succinyltransferase; KGDH, a-ketoglutarate dehydrogenase; MMP, matrix metalloproteinase; mTOR, mammalian target of rapamycin; PDH, pyruvate dehydrogenase; ROS, reactive oxygen species; XDH, xanthine dehydrogenase.