IndraLab

"Targeting USP14 and UCHL5 by small compounds has been shown to overcome bortezomib resistance and induce apoptosis in multiple myeloma ( Tian et al., 2014 )."

"For elderly patients with dysregulated protein homeostasis, high levels of UCHL5 inhibited proteasome activity, and were determined to promote the apoptosis of cancer cells (28)."

"b-AP15 is a specific UCHL5 and USP14 inhibitor identified from a screening of small molecules that induce the lysosomal apoptosis pathway."

"Our recent study exemplifies the feasibility of such an approach : specifically, we showed that blockade of 19S associated DUBs USP14 and UCHL5 with a small-molecule inhibitor (bAP15 and VLX1570) induces apoptosis in MM cells and overcome bortezomib resistance, with a favorable toxicity profile."

"Therefore, our current research may allow targeting UCHL5 and USP14 in 19S regulatory particle for anti-cancer drug development.b-AP15 was reported to inhibit tumor cell growth and induce cell apoptosis, and displays anti-tumor role in multiple tumor cell models without inhibiting 26S proteasomes proteolytic activities."

"Additionally, UCHL5 knockout led to an increase in apoptosis markers such as Cleaved Caspase-3 and BAX, accompanied by a decrease in the anti-apoptotic protein BCL-2, indicating that UCHL5 promotes tumor cell survival in cervical cancer by regulating apoptosis pathways."

"Other studies have also found that b-AP15 inhibition of USP14 and UCHL5 triggers apoptosis in MM cell lines in a time dependent and dose dependent manner.77 Similar cytotoxic effects, as those seen with b-AP15 treatment, occur within myeloma cells when treated with an alternative DUB inhibitor, copper pyrithione.77 Targeting E1 ubiquitin activating enzyme and E3 ubiquitin ligases has synergistic activity with bortezomib on cell lines.78, 79 An inhibitor of USP7, P5091, can interfere with ubiquitin binding and overcome bortezomib resistance invitro and invivo.80 NIMA related kinase 2 (NEK2) overexpression is associated with resistance to multiple drugs and poor prognosis in MM, and NEK2 inhibitor has been shown to decrease proteasome activity.81 Further investigation into its role in Bortezomib resistance is required."