shikonin and 1-4-naphthoquinone

Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) > 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 ± 0.01 to 1.33 ± 0.05 μM toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Bel7402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti-MDR agents.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Naphthoquinones; Oximes; Structure-Activity Relationship; Sulfur

Topics: Antineoplastic Agents; cdc25 Phosphatases; Cell Line, Tumor; Cell Survival; Enzyme Inhibitors; Humans; MAP Kinase Kinase 7; Models, Molecular; Molecular Docking Simulation; Naphthoquinones

We recently discovered that 5, 8-O-dimethyl acylshikonin derivatives displayed the selectivity towards MCF-7 and no toxicity to normal cells. Herein, a series of the corresponding 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were synthesized starting from shikonin. In vitro evidence of the cytotoxicities indicated that most of thecompounds were more active than or comparative to shikonin and retained the selectivity against MCF-7, MDA-MB-231 besides no toxicity in the normal cells. Also, in vivo anticancer activity of the positional isomers 5p, 6c further showed that 6-isomers of 5, 8-O-dimethyl acylshikonin derivatives were more active than their corresponding 2-isomers. Thus, we may conclude that the position of the side chain of shikonin attached to 5,8-dimethoxy -1,4-naphthoquinone is associated with the antitumor activity.

Topics: Acylation; Animals; Antineoplastic Agents; Cell Survival; Drug Screening Assays, Antitumor; Female; Fibroblasts; Humans; Inhibitory Concentration 50; Isomerism; Male; Mice; Naphthoquinones; Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured