Anticancer efficacy and absorption, distribution, metabolism, and toxicity studies of aspergiolide A in early drug development.
Since the first anthracycline was discovered, many other related compounds have been studied in order to overcome its defects and improve efficacy. In the present paper, we investigated the anticancer effects of a new anthracycline, aspergiolide A (ASP-A), from a marine-derived fungus in vitro and in vivo, and we evaluated the absorption, distribution, metabolism, and toxicity drug properties in early drug development. We found that ASP-A had activity against topoisomerase II that was comparable to adriamycin. ASP-A decreased the growth of various human cancer cells in vitro and induced apoptosis in BEL-7402 cells via a caspase-dependent pathway. The anticancer efficacy of ASP-A on the growth of hepatocellular carcinoma xenografts was further assessed in vivo. Results showed that, compared with the vehicle group, ASP-A exhibited significant anticancer activity with less loss of body weight. A pharmacokinetics and tissue distribution study revealed that ASP-A was rapidly cleared in a first order reaction kinetics manner, and was enriched in cancer tissue. The maximal tolerable dose (MTD) of ASP-A was more than 400 mg/kg, and ASP-A was not considered to be potentially genotoxic or cardiotoxic, as no significant increase of micronucleus rates or inhibition of the hERG channel was seen. Finally, an uptake and transport assay of ASP-A was performed in monolayers of Caco-2 cells, and ASP-A was shown to be absorbed through the active transport pathway. Altogether, these results indicate that ASP-A has anticancer activity targeting topoisomerase II, with a similar structure and mechanism to adriamycin, but with much lower toxicity. Nonetheless, further molecular structure optimization is necessary.
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Yuanyuan
Y
Wang
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Xin
X
Qi
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Dehai
D
Li
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Tianjiao
T
Zhu
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Xiaomei
X
Mo
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, People's Republic of China.
Jing
J
Li
D065567:Absorption, Physiological; D000818:Animals; D000880:Anthraquinones / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy; D061986:MCF-7 Cells; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D059005:Topoisomerase II Inhibitors; C542894:aspergiolide A; D004250:DNA Topoisomerases, Type II
ADMT; anthracyclines; anticancer; aspergiolide A; drug activity