Cancer therapy with beta-lapachone.
Beta-lapachone is an ortho naphthoquinone, originally isolated from a tree whose extract has been used medicinally for centuries. Recent investigations suggest its potential application against numerous diseases. Its lethality at micromolar ( m) concentrations against a variety of cancer cells in culture indicates its potential against tumor growth. A few experiments with positive results have been performed that apply the compound to tumors growing in animals. Particularly promising is the remarkably powerful synergistic lethality between beta-lapachone and taxol against several tumor cell lines implanted into mice; the mice did not appear to be adversely affected. Enhanced lethality of X-rays and alkylating agents to tumor cells in culture was reported when beta-lapachone was applied during the recovery period, because of inhibition of DNA lesion repair. Clinical trials are still to be initiated. The detailed mechanism of cell death induced by beta-lapachone remains for investigation. DNA topoisomerase I was the first biochemical target of beta-lapachone to be discovered, although its role in cell death is not clear. A proposed mechanism of cell death is via activation of a futile cycling of the drug by the cytoplasmic two-electron reductase NAD(P) H: quinone oxidoreductase, also known as NQO1, DT-diaphorase and Xip3. Death of NQO1 expressing cells is prevented by the NQO1 inhibitor dicoumarol, and cells with low NQO1 are resistant. At higher drug concentrations the production of reactive oxygen species (ROS) appears to be responsible. Furthermore, this process is p53- and caspase- independent. Either apoptotic or necrotic cell death can result, as reported in various studies performed under differing conditions. Beta-lapachone is one of a few novel anticancer drugs currently under active investigation, and it shows promise for chemotherapy alone and especially in combinations.
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA. pardee@mbcrr.harvard.edu
Arthur B
AB
Pardee
You Zhi
YZ
Li
Chiang J
CJ
Li
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001938:Brazil; D004359:Drug Therapy, Combination; D006801:Humans; D009285:Naphthoquinones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010946:Plants, Medicinal / Q000737:chemistry
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D009285:Naphthoquinones; C014638:beta-lapachone