Abstract
Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 μM (p < 0.01) and buclizine with a Kd of 433μM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.
Highlights
Cancer is one of the leading causes of death all over the world
Afterwards, defined molecular dockings of promethazine, hydroxyzine, levomepromazine and buclizine were performed three times with a grid laid around human Translationally controlled tumor protein (TCTP) residues found by blind docking (Table 2)
Levomepromazine and buclizine bound to the same sites as promethazine and hydroxyzine, respectively (Figure 2)
Summary
Cancer is one of the leading causes of death all over the world. Traditionally, surgery, chemotherapy and radiotherapy are main treatment options and cytotoxic drugs are indispensable in the armory to destroy tumor cells [1]. Many cytotoxic agents reveal side effects such as bone marrow suppression, gastrointestinal tract lesions, hair loss, nausea etc., because these agents are active on both, proliferating, malignant tumor and healthy, normal cells These drugs induce cell death in tumors, and in normal cells [2, 3]. Since cytotoxic drugs lack sufficient tumor selectivity, they frequently cannot cure patients due to non-tolerable high side effects that prevent the application of drug doses high enough to sustainably kill all cells of a tumor Another concept is differentiation therapy, which aims at re-activation of endogenous differentiation programs in cancer cells with subsequent cellular maturation and loss of the aggressive tumor phenotype [4]. ATRA hypophosphorylated RARα inhibiting cellular proliferation and inducing osteoblastic differentiation [8]
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