ABSTRACT
Microtubule dynamics are critical for spindle assembly and chromosome segregation during cell division. Pharmacological inhibition of microtubule dynamics in cells causes prolonged mitotic arrest, resulting in apoptosis, an approach extensively employed in treating different types of cancers. The present study reports the synthesis of thirty-two novel bis-amides (SSE1901-SSE1932) and the evaluation of their antiproliferative activities. N-(1-oxo-3-phenyl-1-(phenylamino)propan-2-yl)benzamide (SSE1917) exhibited the most potent activity with GI50 values of 0.331 ± 0.01 µM in HCT116 colorectal and 0.48 ± 0.27 µM in BT-549 breast cancer cells. SSE1917 stabilized microtubules in biochemical and cellular assays, bound to taxol site in docking studies, and caused aberrant mitosis and G2/M arrest in cells. Prolonged treatment of cells with the compound increased p53 expression and triggered apoptotic cell death. Furthermore, SSE1917 suppressed the growth of both mouse and patient-derived human colon cancer organoids, highlighting its potential therapeutic value as an anticancer agent.
Subject(s)
Antineoplastic Agents , Tubulin Modulators , Tubulin , Animals , Humans , Mice , Amides/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/metabolism , Apoptosis , Cell Line, Tumor , Cell Proliferation , Microtubules/metabolism , Mitosis , Tubulin/drug effects , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
Microtubules are dynamic structures that form spindle fibers during cell division; pharmacological inhibition of microtubule dynamics arrests cells in mitosis, leading to apoptosis, and they have been extensively used to treat various cancers. However, the efficacy of such drugs is often limited by multidrug resistance. This study synthesized and evaluated 30 novel derivatives of podophyllotoxin, a natural antimitotic compound, for their antiproliferative activities. Compound SSE1806 exhibited the most potent antiproliferative activity with GI50 values ranging from 1.29 ± 0.01 to 21.15 ± 2.1 µM in cancer cell lines of different origins; it directly inhibited microtubule polymerization, causing aberrant mitosis and G2/M arrest. Prolonged treatment with SSE1806 increased p53 expression, induced cell death in monolayer cultures, and reduced the growth of mouse- and patient-derived human colon cancer organoids. Importantly, SSE1806 overcame multidrug resistance in a cell line overexpressing MDR-1. Thus, SSE1806 represents a potential anticancer agent that can overcome multidrug resistance.
ABSTRACT
High expression of the transcriptional regulator EVI1 encoded at the MECOM locus at 3q26 is one of the most aggressive oncogenic drivers in acute myeloid leukemia (AML) and carries a very poor prognosis. How EVI1 confers leukemic transformation and chemotherapy resistance in AML is subject to important ongoing clinical and experimental studies. Recent discoveries have revealed critical details on genetic mechanisms of the activation of EVI1 overexpression and downstream events of aberrantly high EVI1 expression. Here we review and discuss aspects concerning the protein interactions of EVI1 and the related proteins MDS-EVI1 and ΔEVI1 from the perspective of their potential for therapeutic intervention.