The heparanase inhibitor PG545 is a potent anti-lymphoma drug: Mode of action.

Abstract It is now well recognized that heparanase, an endo -β-D-glucuronidase capable of cleaving heparan sulfate (HS) side chains at a limited number of sites, promotes tumorigenesis by diverse mechanisms. Compelling evidence strongly implies that heparanase is a viable target for cancer therapy, thus encouraging the development of heparanase inhibitors as anti-cancer therapeutics. Here, we examined the efficacy and mode of action of PG545, an HS-mimetic heparanase inhibitor, in human lymphoma. We found that PG545 exhibits a strong anti-lymphoma effect, eliciting lymphoma cell apoptosis. Notably, this anti-lymphoma effect involves ER stress response that was accompanied by increased autophagy. The persistent ER stress evoked by PG545 is held responsible for cell apoptosis because apoptotic cell death was attenuated by an inhibitor of PERK, a molecular effector of ER stress. Importantly, PG545 had no such apoptotic effect on naïve splenocytes, further encouraging the development of this compound as anti-lymphoma drug. Surprisingly, we found that PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity (i.e., Raji), indicating that the drug also exerts heparanase-independent function(s) that together underlie the high potency of PG545 in preclinical cancer models. Highlights • Compelling evidence implies that heparanase is a viable target for cancer therapy. • We examined the mode of action of PG545, an HS-mimetic heparanase inhibitor. • PG545 exhibits a strong anti-lymphoma effect, eliciting lymphoma cell apoptosis. • This anti-lymphoma effect involves ER stress response accompanied by increased autophagy. • PG545 has no such effects on naïve splenocytes, supporting its development as anti-lymphoma drug. • PG545 also elicits apoptosis in lymphoma cells that are devoid of heparanase activity. [ABSTRACT FROM AUTHOR]