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

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.

The mycelium of the Trametes versicolor synn. Coriolus versicolor (Turkey tail mushroom) exhibit anti-melanoma activity in vitro

“…We found PCB to have an additive effect with T. versicolor mycelium extract in the lowest concentration and to have an antagonistic effect in higher concentrations of the drug ( Table 1 ). We previously reported a similar dose-dependent differential response for other treatment combinations [ 51 ]. ABT-263 exhibited an antagonistic effect with T. versicolor mycelium extract ( Table 1 ), while paclitaxel exhibited moderate synergism in the lowest concentration and antagonism in higher concentrations ( Table 1 ).…”

“…For the pair of drugs, CI > 1.3 indicates antagonism, CI = 1.1–1.3 indicates moderate antagonism, CI = 0.9–1.1 indicates an additive effect, CI = 0.8–0.9 indicates slight synergism, CI = 0.6–0.8 indicates moderate synergism, CI = 0.4–0.6 indicates synergism, and CI = 0.2–0.4 indicates strong synergism [ 52 – 54 , 51 ].…”

Silicon-tethered colchicine aryne cyclo-adduct as a potent molecule for the abrogation of epithelial to mesenchymal transition via modulating cell cycle regulatory CDK-2 and CDK-4 kinases

“…It has a narrow therapeutic index and is highly toxic to normal cells. Many of its derivatives have been reported as anticancer agents (6,(17)(18)(19).…”

Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function

“…Due to colchicine's low therapeutic index and severe cytotoxicity, various colchicine analogues have been synthesized by modifying the tricyclic-membered rings. Urbaniak et al synthesized 16 novel colchicine derivatives, namely, double- (4-7) or triple-modified (17-28) urethanes, and found that these novel colchicine derivatives (IC 50 range of 1.1-6.4 nM) had higher antiproliferative activity than colchicine (IC 50 = 8.6 nM) by testing the viability of primary breast cancer cells [ 156 ]. Recently, the colchicine analogue combretastatin was found to promote anticancer activity by inhibiting the elongation of MTs [ 157 ].…”