Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study

Urbaniak, Alicja; Jousheghany, Fariba; Pina-Oviedo, Sergio; Yuan, Youzhong; Majcher-Uchanska, Urszula; Klejborowska, Greta; Moorjani, Anika; Monzavi-Karbassi, Behjatolah; Huczynski, Adam; Chambers, Timothy C.

doi:10.1002/JBT.22487

Title

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study

Author

Urbaniak, Alicja

Jousheghany, Fariba

Pina-Oviedo, Sergio

Yuan, Youzhong

Majcher-Uchanska, Urszula

Klejborowska, Greta

Moorjani, Anika

Monzavi-Karbassi, Behjatolah

Huczynski, Adam

Chambers, Timothy C.

Abstract

Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3-9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.

Language

English

Source (journal)

Journal of biochemical and molecular toxicology. - Deerfield Beach, Fla

Publication

Deerfield Beach, Fla : 2020

ISSN

1095-6670

DOI

10.1002/JBT.22487

Volume/pages

34 :6 (2020) , 14 p.