Tubulin-binding anticancer polysulfides induce cell death via mitotic arrest and autophagic interference in colorectal cancer

Diagnosis of Biological Activities by Mass Spectrometry

“…The complex protein-ligand is analyzed by Mass Spectrometry and the direct detection of the ligand reflects its potential inhibition activity against the target. Screening tests have already been developed for the ligands of tubulin [2,3], dihydroxyfolate reductase (DHFR) [4] and recently for reversible and irreversible ligands of CDC25 phosphatases (isoforms A et C) [5]. This approach demonstrates its effectiveness with Madagascar periwinkle for tubulin, with Colchicum and green tea for DHFR and some promising plants are currently evaluated on CDC25s.…”

Inspired by Nature: Redox Modulators and Natural Nanoparticles

“…Compounds such as allicin and polysulfides found in many Allium plants, for instance, can interact with the "cellular thiolstat" [4]. Such agents are moderately reactive, affect numerous cellular processes, exhibit pronounced antioxidant and also cyto-toxic activities and, therefore, have been linked to certain preventive or even therapeutic actions [5][6][7][8][9][10]. Together, a balanced cocktail of such biologically active nutritional components may provide a promising and also more applicable alternative to extensive medication.…”

Targeted Anticancer Strategies with Garlic Derivatives

“…Generally recognized as inducers of mitotic arrest and cell death, yet their activities appear broad, without specific intracellular targets. Here we suggest their potential as targeted agents and cancer types as suitable responders, taking the garlic-derived diallyl tetrasulfides (DATTS) and its most effective hemi-synthetic derivative di-benzyl tetrasulfide (DBTTS) as lead compounds [1][2][3][4]. We discovered DATTS/DBTTS as reversible tubulin binders, via redox modulation of the tubulin thiols.…”

“…Translating our investigations to cellular models, we selected cancer types of the gastrointestinal tract (colorectal cancer, CRC) and the blood (acute forms of leukemia), being both highly proliferating and exposed in vivo to appropriate and stable concentrations of sulfur compounds. In both cell types, DATTS/DBTTS binding compromises the microtubule machinery, thereby inducing mitotic arrest and apoptosis [1][2][3][4]. Of note, a higher expression of genes coding specific tubulin isoforms in KRAS-mutated CRC SW480 and SW620 correlates with faster cell proliferation and the increased susceptibility to these compounds vs. the most resistant BRAFmutated HT-29 [1].…”

“…In both cell types, DATTS/DBTTS binding compromises the microtubule machinery, thereby inducing mitotic arrest and apoptosis [1][2][3][4]. Of note, a higher expression of genes coding specific tubulin isoforms in KRAS-mutated CRC SW480 and SW620 correlates with faster cell proliferation and the increased susceptibility to these compounds vs. the most resistant BRAFmutated HT-29 [1]. The resistance in HT-29 associated with the impairment of the autophagic flux concomitant with the prolonged mitotic block and characterized by p62 protein accumulation.…”