Novel Tubulin Polymerization Inhibitors Overcome Multidrug Resistance and Reduce Melanoma Lung Metastasis

Abstract

Purpose To evaluate abilities of 2-aryl-4-benzoyl-imidazoles (ABI) to overcome multidrug resistance (MDR), define their cellular target, and assess in vivo antimelanoma efficacy. Methods MDR cell lines that overexpressed P-glycoprotein, MDR-associated proteins, and breast cancer resistance protein were used to evaluate ABI ability to overcome MDR. Cell cycle analysis, molecular modeling, and microtubule imaging were used to define ABI cellular target. SHO mice bearing A375 human melanoma xenograft were used to evaluate ABI in vivo antitumor activity. B16-F10/C57BL mouse melanoma lung metastasis model was used to test ABI efficacy to inhibit tumor lung metastasis. Results ABIs showed similar potency to MDR cells compared to matching parent cells. ABIs were identified to target tubulin on the colchicine binding site. After 31 days of treatment, ABI-288 dosed at 25 mg/kg inhibited melanoma tumor growth by 69%; dacarbazine at 60 mg/kg inhibited growth by 52%. ABI-274 dosed at 25 mg/kg showed better lung metastasis inhibition than dacarbazine at 60 mg/kg. Conclusions This new class of antimitotic compounds can overcome several clinically important drug resistant mechanisms in vitro and are effective in inhibiting melanoma lung metastasis in vivo, supporting their further development.

Discovery of Novel Second Mitochondria-Derived Activator of Caspase Mimetics as Selective Inhibitor of Apoptosis Protein Inhibitors

“…The antiproliferation effect against cancer cells of all UC compounds was first screened in vitro by using the MTS assay as described previously Wang et al, 2012;Xiao et al, 2013). Then the IC 50 values of selected hits were tested through the sulforhodamine B assay as reported before .…”

RAGE and Its Ligands in Melanoma

“…S100B also interacts with many components of the cytoskeleton such as tubulin [149,150], the actin binding protein caldesmon [151] or the small GTPase Rac1 and the cdc42 effector IQGAP1 [152]. All these proteins play important function in malignant melanoma [153][154][155] and increases in S100B levels could therefore favor increases in cell proliferation, migration and invasion through their modulation. S100B could also play a role in melanoma cell growth through the activation of the Nuclear Dbf2 related (ndr) kinase [156][157][158] and the interaction with the phosphoprotein AHNAK/desmoyokin [159][160][161].…”

Discovery of Novel Tubulin Polymerization Inhibitors and Survivin Inhibitors as Potential Anticancer Agents

“…[108,[112][113][114][115][116] Compared with existing tubulin-targeting agents such as paclitaxel, colchicine, or vinblastine, ABI compounds have comparable in vitro and in vivo potency but can effectively circumvent several clinically relevant multidrug resistant mechanisms, including drug resistance mediated by Pgp, multidrug resistance-associated proteins (MRPs), and breast cancer resistant proteins (BCRP). [113][114] ABI compounds have also shown excellent oral bioavailability [113], a potential advantage over existing tubulin inhibitors which can only be administrated by intravenous injection. To further optimize the potency of ABI analogues and to gain further insight in their structure-activity relationships (SAR), we designed and synthesized several new series of ABI analogs (summarized in Figure 3-1) by introducing three major changes to the parental ABI scaffold as described below.…”

“…As shown in Table 3-1, compound 5a (average IC50 = 18 nM) maintained potent activity in most cancer cells compared with compound 5da [108,114](average IC50 = 10 nM) which has a methyl substitution on A ring para position. Introducing a larger isopropyl group (5b, average IC50 = 254 nM) into this position on the A ring caused a 20-fold decrease of potency compared with compound 5da.…”

“…We have previously shown that the parent ABI analogs can effectively overcome a variety of clinically relevant multidrug resistant mechanisms including Pgp-mediated drug resistance. [113][114] To determine whether the new RABI analogs maintain this ability, we compared the activity of the RABI compounds against multidrug-resistant melanoma cells (MDA-MB-435/LCCMDR1) and their parental nonresistant cancer cells (MDA-MB-435). This pair of cell lines have been well validated and widely used to assess abilities of drugs overcoming Pgp-mediated multidrug resistance.…”