Novel Triazole Ribonucleoside Down-Regulates Heat Shock Protein 27 and Induces Potent Anticancer Activity on Drug-Resistant Pancreatic Cancer

Abstract

A series of novel 3-arylethynyltriazolyl ribonucleosides were synthesized and assessed for their anticancer activity on the drug-resistant pancreatic cancer cell line MiaPaCa-2. Among them, one compound exhibited potent apoptosis-inducing properties and anticancer activity against the pancreatic cancer model MiaPaCa-2 both in vitro and in vivo with no adverse effects. This compound did not inhibit DNA synthesis and therefore does not resemble the clinical drug gemcitabine. It did, however, significantly down-regulate the expression of heat shock protein 27 (Hsp27), a small molecular chaperone playing an important role in drug resistance and highly expressed in drug-resistant cancer forms, and thus represents the first small molecular anticancer lead with such a mode of action.

RP101 (brivudine) binds to heat shock protein HSP27 (HSPB1) and enhances survival in animals and pancreatic cancer patients

“…Furthermore, knock-out of HSPB1 reduces chemoresistance (Mori-Iwamoto et al 2007). Importantly, HSPB1 is up-regulated across many types of cancer, including prostate (Song et al 2004), colorectal (Zhao et al 2007), liver (Feng et al 2005), breast (Kang et al 2008), skin ), bladder (Kamada et al 2007;Rane et al 2003), eye (Kase et al 2009), ovarian (Xia et al 2009), and pancreas (Xia et al 2009). In some of these cancers, such as ovarian, liver, bladder, and eye, HSPB1 is also implicated in chemoresistance (Nitiss 2009).…”

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

“…A recent example of a new class of HSF1 modulators was provided by Peng and co-workers who modified a triazole nucleoside scaffold that was previously found to downregulate the expression of another HSF1 target, Hsp27 [295,296]. After synthesizing variants, a compound with greater antiproliferative activity was obtained (Fig.…”

Morpho-Physiological Traits Linked to High Temperature Stress Tolerance in Tomato <i>(S. lycopersicum L.)</i>

“…Exposure to temperatures above 25˚C significantly reduces fruit number, fruit weight and seed number per fruit [16]. Heat shock at extremely high temperature (≥45˚C) can lead to programmed cell death (PCD), release of cytochrome c and activation of caspase-like enzymes [17]. Plant reproductive organs are clearly more sensitive to heat stress than vegetative parts [18] [19].…”