Carbamate Derivatives of Colchicine Show Potent Activity toward Primary Acute Lymphoblastic Leukemia and Primary Breast Cancer Cells: In Vitro and Ex Vivo Study

Abstract

Colchicine (COL) is the major alkaloid isolated from the plant Colchicum autumnale. It shows strong therapeutic effects towards various types of cancer. Its biological activity is related to its ability to bind to tubulin causing microtubule depolymerization, mitotic arrest, and cell death. The colchicine binding site is an attractive target for potential tubulin polymerization destabilizers. Indeed, a large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. The identification of new therapeutics based on COL structure is warranted due to the toxicity of COL towards normal cells. In order to increase potency and reduce toxicity against normal cells, while retaining the activities in the nanomolar range, a library of novel COL analogs, namely N‐carbamates of N‐deacetyl‐4‐(bromo/chloro/iodo)thiocolchicine, has been synthesized (Fig. 1).COL and several of the derivatives arrested MCF‐7 cells in mitosis, and caused microtubule depolymerization. Compounds were then tested against two types of primary cancer cells; adult acute lymphoblastic leukemia (ALL) cells, and human breast cancer (BC) cells derived from newly excised human tumor tissue. These represent more clinically relevant drug screening models compared to established cell lines. Four novel colchicine derivatives showed higher activity towards primary ALL cells (IC50 = 1.1 ± 0.5 to 6.4 ± 1.4 nM) and nine were more potent towards primary BC cells (IC50 = 2.3 ± 0.0 to 10.3 ± 4.6 nM) compared to COL (IC50 = 8.6 ± 0.2 nM and 11.7 ± 3.1 nM, respectively) in cell viability assays. COL and two of the most active derivatives were also shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants derived from residual invasive ductal carcinoma and invasive mucinous carcinoma. The present findings indicate that the COL derivatives described here constitute promising lead compounds for targeting acute lymphoblastic leukemia and different subtypes of breast cancer.Support or Funding InformationThe present study was funded by a grant (to TCC) from the Arkansas Breast Cancer Research Program. Financial support by grant (to AH. UM, GK) of the Polish National Science Centre (NCN) – No. 2016/21/B/ST5/00111 is gratefully acknowledged.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.