Anticancer activities of vitamin K3 analogues

• Published in: Investigational new drugs 2020-04, Vol.38 (2), p.378-391
• Main Authors: Wellington, Kevin W., Hlatshwayo, Vincent, Kolesnikova, Natasha I., Saha, Sourav Taru, Kaur, Mandeep, Motadi, Lesetja R.
• Format: Article
• Language: English
• Subjects: Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Aromatic compounds; Biotechnology; Breast cancer; Cancer; Catalysts; Cell cycle; Cell Cycle - drug effects; Cell Line; Cell Survival - drug effects; Cervix; Chemical synthesis; Chemotherapy; Etoposide; Fetuses; Fibroblasts; Fibroblasts - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Hepatocytes; Humans; Laccase; Liver cancer; Medicine; Medicine & Public Health; Melanoma; Membrane potential; Menadione; Mitochondria; Neoplasms - drug therapy; Oncology; Pharmacology/Toxicology; Preclinical Studies; Prostate cancer; Reactive oxygen species; Reactive Oxygen Species - metabolism; Sulfides; Thiols; Tumor cell lines; Vitamin K 3 - analogs & derivatives; Vitamin K 3 - pharmacology
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00855-8

Summary In a previous study we reported on the synthesis of 1,4-naphthoquinone-sulfides by thiolation of 1,4-naphthohydroquinones with primary aryl and alkyl thiols using laccase as catalyst. These compounds were synthesized as Vitamin K3 analogues. Vitamin K3 (VK3; 2-methyl-1,4-naphthoquinone; menadione) is known to have potent anticancer activity. This investigation reports on the anticancer activity of these VK3 analogues against TK10 renal, UACC62 melanoma, MCF7 breast, HeLa cervical, PC3 prostate and HepG2 liver cancer cell lines to evaluate their cytostatic effects. A 1,4-naphthohydroquinone derivative exhibited potent cytostatic effects (GI 50  = 1.66–6.75 μM) which were better than that of etoposide and parthenolide against several of the cancer cell lines. This compound produces reactive oxygen species and disrupts the mitochondrial membrane potential in the MCF7 breast cancer cell line which is an indication that the cells undergo apoptosis. The 1,4-naphthoquinone sulfides also had potent cytostatic effects (GI 50  = 2.82–9.79 μM) which were also better than that of etoposide, parthenolide and VK3 against several of the cancer cell lines. These compounds are generally more selective for cancer cells than for normal human lung fetal fibroblasts (WI-38). They also have moderate to weak cytostatic effects compared to etoposide, parthenolide and VK3 which have potent cytostatic effects against WI-38. One analogue induces apoptosis by activating caspases without arresting the cell cycle in the MCF7 breast cancer cell line. These results inspire further research for possible application in cancer chemotherapy.