Substituted 2-hydroxy-N-(arylalkyl)benzamide sensitizes cancer cells to metabolic stress by disrupting actin cytoskeleton and inhibiting autophagic flux.
N-((R)-1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (Compound 6k), was recently isolated during the preparation of amino acids esters with salicylanilides. We show here that 6k disrupts the dynamics of actin cytoskeleton in human melanoma cells, affecting processes essential for the maintenance and expansion of tumours such as cell adhesion, motility, proliferation, vesicular transport, and autophagic flux. We demonstrated that inhibition of autophagy by 6k increased the sensitivity of melanoma cells to metabolic stress induced by rotenone or nutrient starvation and potentiated the anti-proliferative activity of small molecule multikinase inhibitor sorafenib. Since autophagy plays an important role in survival of cancer cells subjected to chemotherapy, the above mentioned properties are interesting from clinical point of view as 6k could promote metabolic stress within the tumour microenvironment and potentiate the effect of cytostatics in combination therapy.
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Pekařská 53, 656 91 Brno, Czech Republic.
Gabriela
G
Páchniková
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital Brno, Pekařská 53, 656 91 Brno, Czech Republic.
Stjepan
S
Uldrijan
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.
Aleš
A
Imramovský
Laboratory of Growth Regulators, Faculty of Science, Palacky University and Institute of Experimental Botany ASCR, Šlechtitelů 27, 78371 Olomouc, Czech Republic.
Vladimír
V
Kryštof
Department of Biology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Electronic address: ipokorna@med.muni.cz.
Iva
I
Slaninová
D008841:Actin Cytoskeleton / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000077157:Sorafenib; D013312:Stress, Physiological; D014945:Wound Healing
D000970:Antineoplastic Agents; D001549:Benzamides; C000616611:N-(1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D010649:Phenylalanine; D000077157:Sorafenib
Actin; Autophagy; Melanoma; Metabolic stress; Sorafenib; Substituted 2-hydroxy-N-(arylalkyl)benzamide