Pharmacological Role of a Novel Dual-Targeting Hdacs/Microtubule Inhibitor 21-277 Inhibits Human Cancer Cells Growth in Vitro and in Vivo

Although the current cancer target therapy can significantly improve patients’ survival rate, some patients still develop drug resistance after using certain targeting agents. Hence, it is urgent and necessary to development new anti-cancer drug with different mechanisms. It has been demonstrated that histone deacetylase (HDAC) is highly expressed in many cancer cells that makes the HDAC inhibitors become the potent anti-cancer drugs. Additionally, cancer cells are rapidly dividing cells and microtubules play a major role in mitosis, thus microtubules also serves as a powerful target in anti-cancer drug development. The aim of this proposal is to develop a 1-benzyl-indoles derivative, which is a dual target inhibitor targeting both HDAC and microtubule, into a potential anti-cancer drug. Our preliminary studies showed the 1-benzyl-indoles derivative 21-277 has inhibitory effects for both HDAC and microtubule. Our preliminary data also indicated that 21-277 showed striking growth inhibition in various cancer cells, especially in human prostate cancer cells and leukemia cells. 21-277 induced G2/M phase cell cycle arrest, and the mitotic index protein MPM2 was increased after 21-277 treatments in a dose-dependent manner. 21-277 further induced y-H2AX and PARP cleavage, indicating 21-277 could induce cell undergo apoptosis. We performed KINOMEscan (DiscoveRx) analysis with 21-277 for nearly 100 human protein kinases. The result indicated 21-277 does not involve in protein kinase activity but primarily targeting HDAC and microtubule. Our prostate cancer xenograft further demonstrated that 21-277 can reduce tumor size without bodyweight loss, indicating 21-277 has tumor suppressive effect and low toxicity. The following aims are proposed to accomplish our goal: Aim 1: To evaluate the therapeutic effect of 21-277 for solid tumor using prostate cancer cells and investigate the mechanism of action of 21-277 in vitro and in vivo. Aim 2: To evaluate the therapeutic effect of 21-277 in leukemia and examine the mechanism of action of 21-277 in vitro and in vivo. Aim 3: To evaluate the anti-tumor effect of drug combination by combining 21-277 with current clinical anti-cancer drugs. We believe this project will shed new light on anti-cancer drug development.