Novel LIMK2 inhibitor blocks Panc-1 tumor growth in a mouse xenograft model

Abstract

LIM kinases (LIMKs) are important cell cytoskeleton regulators that play a prominent role in cancer manifestation and neuronal diseases. The LIMK family consists of two homologues, LIMK1 and LIMK2, which differ from one another in expression profile, intercellular localization, and function. The main substrate of LIMK is cofilin, a member of the actin-depolymerizing factor (ADF) protein family. When phosphorylated by LIMK, cofilin is inactive. LIMKs play a contributory role in several neurodevelopmental disorders and in cancer growth and metastasis. We recently reported the development and validation of a novel LIMK inhibitor, referred to here as T56-LIMKi, using a combination of computational methods and classical biochemistry techniques. Here we report that T56-LIMKi inhibits LIMK2 with high specificity, and shows little or no cross-reactivity with LIMK1. We found that T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and thus inhibits growth of several cancerous cell lines, including those of pancreatic cancer, glioma and schwannoma. Because the most promising in-vitro effect of T56-LIMKi was observed in the pancreatic cancer cell line Panc-1, we tested the inhibitor on a nude mouse Panc-1 xenograft model. T56-LIMKi reduced tumor size and p-cofilin levels in the Panc-1 tumors, leading us to propose T56-LIMKi as a candidate drug for cancer therapy.

JG6, a novel marine-derived oligosaccharide, suppresses breast cancer metastasis via binding to cofilin

“…Molecular imaging of JG6 by conjugating to fluorescein could be an option. Our findings may highlight the strategy of targeting actin-binding proteins, such as cofilin or cofilin regulators such as LIMK1/2[33, 34], rather than actin itself for cancer therapy.…”

LIM Kinase Inhibitor Pyr1 Reduces the Growth and Metastatic Load of Breast Cancers

“…LIMKs are considered as emerging targets for cancer therapy (21), and an increasing number of inhibitors is reported in the literature (2,(22)(23)(24)(25)(26)(27)(28). Among these inhibitors, few, if any, fulfill the three criteria that are important for in vivo experiments, that is, high selectivity, complete characterization of the effects on both actin and microtubule dynamics, and knowledge of toxicity on animals.…”

Latest progress in tyrosine kinase inhibitors

“…IKK regulates mTORC2 activity including phosphorylating AKT at the serine 473 and actin cytoskeleton reorganization, which is controlled by LIM kinases. The LIM kinases are promising oncotarget in several types of cancer [11-13]. The main substrate of LIM kinase is cofilin, an actin-depolymerizing factor.…”

“…LIMK2 increases resistance to chemotherapeutic agents in neuroblastoma cells by regulating drug-induced cell cycle arrest [15]. A LIMK inhibitor, T56-LIMKi, inhibits LIMK2 with high specificity, while not inhibiting LIMK1 [13]. T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and inhibits growth of glioma, schwannoma and pancreatic cancer.…”

“…T56-LIMKi decreases phosphorylated cofilin (p-cofilin) levels and inhibits growth of glioma, schwannoma and pancreatic cancer. T56-LIMKi reduced tumor size and p-cofilin levels in the pancreatic tumors [13]. Also, thioredoxin inhibition is emerging as attractive strategy [16-18] especially employing already existing drugs such as Disulfiram for novel use [16, 19, 20].…”