Anti-leukemia activity of a Hsp70 inhibitor and its hybrid molecules

Abstract

In this study we examined the anti-leukemia activity of a small molecule inhibitor of Hsp70 proteins, apoptozole (Az), and hybrids in which it is linked to an inhibitor of either Hsp90 (geldanamycin) or Abl kinase (imatinib). The results of NMR studies revealed that Az associates with an ATPase domain of Hsc70 and thus blocks ATP binding to the protein. Observations made in the cell study indicated that Az treatment promotes leukemia cell death by activating caspase-dependent apoptosis without affecting the caspase-independent apoptotic pathway. Importantly, the hybrids composed of Az and geldanamycin, which have high inhibitory activities towards both Hsp70 and Hsp90, exhibit enhanced anti-leukemia activity relative to the individual inhibitors. However, the Az and imatinib hybrids have weak inhibitory activities towards Hsp70 and Abl, and display lower cytotoxicity against leukemia cells compared to those of the individual constituents. The results of a mechanistic study showed that the active hybrid molecules promote leukemia cell death through a caspase-dependent apoptotic pathway. Taken together, the findings suggest that Hsp70 inhibitors as well as their hybrids can serve as potential anti-leukemia agents.

Quantum superconductor-insulator transition in titanium monoxide thin films with a wide range of oxygen contents

“…Thus, it would be more appropriate to describe the transition as a superconductor-metal-insulator transition. The similar intervening metallic phase with substantial superconducting fluctuations was also observed in Ta [7] and MoGe [10], but not in TiN [6], which may be related to the different disorder strengths [20,32].…”

“…Superconductor-insulator transition (SIT) as one fascinating example of quantum phase transitions [1] has remained an active topic in recent years. The SIT could be controlled by various non-thermal tuning parameters [2], including disorder [3][4][5][6], thickness [7][8][9], magnetic field [4,7,10,11], chemical composition [12,13], carrier density [4,14], and gate voltage [15,16] in two dimensional (2D) superconductors.…”

“…The other one is a fermionic description [19] where in the insulating phase the Cooper pairs are broken into individually localized electrons corresponding to the amplitude fluctuations. Despite of the efforts for investigating the SIT over last few decades, there are still many open issues, for example, the appearance of a metallic intermediate phase between the superconducting and insulating phases [7,10], different critical exponents signifying different universality classes [7,10,11,20], and various values of critical transition points found in different materials [4,8,9,21]. To clarify these issues and explore more interesting phenomena, researchers are still looking for new SIT systems with widely tunable parameters, as recently reported in LaAlO 3 /SrTiO 3 interface [22] and NbSe 2 monolayer [23].…”

Repurposing drugs to target the malaria parasite unfolding protein response

“…In contrast, all the binder compounds Gilvocarcin V, Apoptozole, MKT077 and VER-155008 have been reported to directly interact with GRP78 or other Hsp70 family member. Gilvocarcin V mechanism of action was associated with GRP78 by cross-linking 26 , and Apoptozole 29 , MKT-077 27 and VER-155008 30 have been previously characterized for binding to recombinant GRP78. As expected, all these four compounds also engaged the Plasmodium chaperone in our two binding assays.…”

Hsp70 inhibitors: Implications for the treatment of colorectal cancer

“…Apoptozole is an imidazole‐based small molecule that promotes apoptosis in cancer cells through targeting of Hsp70 and Hsc70. It associates with ATPase domain of these molecules and thus blocks ATP binding to the protein . In addition, it has been shown that apoptozole enhances the immune response and antibody production against protein antigens, thus could be used as an adjuvant to increase the efficacy of vaccinated antigens .…”