Abstract
The key metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a promising therapeutic target for cancer prevention and treatment. Besides its role in energy homeostasis, AMPK blocks cell cycle, regulates autophagy and suppresses the anabolic processes required for rapid cell growth. AMPK is especially relevant in prostate cancer in which activation of lipogenic pathways correlate with tumor progression and aggressiveness. This study reports the discovery of a new series of 2-oxindole derivatives whose AMPK modulatory ability, as well as the antitumoral profile in prostate cancer cells, was evaluated. One of the assayed compounds, compound 8c, notably activated AMPK in cultured PC-3, DU145 and LNCaP prostate cancer cells. Likewise, compound 8c caused PC-3, DU145 and LNCaP cells viability inhibition. Selective knocking down of α1 or α2 isoforms as well as in vitro assays using human recombinant α1β1γ1 or α2β1γ1 AMPK isoforms revealed that compound 8c exhibit preference for AMPKα1. Consistent with efficacy at the cellular level, compound 8c was potent in suppressing the growth of PC-3 xenograft tumors. In conclusion, our results show that a new 2-oxindole fluorinated derivative exerts potent in vivo antitumor actions against prostate cancer cells, indicating a promising clinical therapeutic strategy for the treatment of androgen-independent prostate cancer.
Highlights
In the last decade, growing evidence about tumors origin and progression has allowed to suggest new additional hallmarks of cancer, which may be involved in the pathogenesis of some and perhaps all types of this disease
Compounds 6a-6c were synthesized by condensation of commercially available 2-oxindole derivatives (4 and 5) with different aromatic aldehydes[30]
The cellular metabolic sensor adenosine monophosphate-dependent kinase (AMPK) has emerged as a key therapeutic target for many cancer types as it controls the metabolic pathways that are usually reprogrammed in cancer cells
Summary
In the last decade, growing evidence about tumors origin and progression has allowed to suggest new additional hallmarks of cancer, which may be involved in the pathogenesis of some and perhaps all types of this disease. A hallmark of prostate cancer is the increased de novo fatty acid and cholesterol synthesis which correlates with tumor progression and poorer prognosis[4,5,6] Targeting these upregulated pathways with inhibitors of key enzymes and associated molecular regulators or by downregulation of lipogenic genes may be a favorable strategy whereby the properties of prostate cancer cells can be exploited for therapeutic gain. From a drug discovery program perspective, crystallographic studies of full-length and truncated AMPK heterotrimeric complexes have provided important insights related to regulatory mechanisms and about the potential binding mode of AMPK modulators[25,26] In this context, A-769662, one of the better-characterized AMPK activator, or the indole, PF-06409577 (1), recently reported by Pfizer for the treatment of diabetic nephropathy, appear as some representative examples[27]. On the basis of these findings, we considered 2-oxindole moiety as an interesting chemical scaffold to explore the way of modulating AMPK and its role in prostate cancer
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