Inhibitory effects of marine-derived DNA-binding anti-tumour tetrahydroisoquinolines on the Fanconi anaemia pathway.
OBJECTIVE
We have previously shown that cells with a defective Fanconi anaemia (FA) pathway are hypersensitive to trabectedin, a DNA-binding anti-cancer tetrahydroisoquinoline (DBAT) whose adducts functionally mimic a DNA inter-strand cross link (ICL). Here we expand these observations to new DBATs and investigate whether our findings in primary untransformed cells can be reproduced in human cancer cells.


METHODS
Initially, the sensitivity of transformed and untransformed cells, deficient or not in one component of the FA pathway, to mitomycin C (MMC) and three DBATs, trabectedin, Zalypsis and PM01183, was assessed. Then, the functional interaction of these drugs with the FA pathway was comparatively investigated.


RESULTS
While untransformed FA-deficient haematopoietic cells were hypersensitive to both MMC and DBATs, the response of FA-deficient squamous cell carcinoma (SCC) cells to DBATs was similar to that of their respective FA-competent counterparts, even though these FA-deficient SCC cells were hypersensitive to MMC. Furthermore, while MMC always activated the FA pathway, the DBATs inhibited the FA pathway in the cancer cell lines tested and this enhanced their response to MMC.


CONCLUSIONS
Our data show that although DBATs functionally interact with DNA as do agents that generate classical ICL, these drugs should be considered as FA pathway inhibitors rather than activators. Moreover, this effect was most significant in a variety of cancer cells. These inhibitory effects of DBATs on the FA pathway could be exploited clinically with the aim of 'fanconizing' cancer cells in order to make them more sensitive to other anti-tumour drugs.
Hematopoietic Innovative Therapies Division, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), E-28040, Madrid, Spain; Pharmamar S.A., Avda. de los Reyes, 1 - Pol. Ind. La Mina, E-28770, Colmenar Viejo, Madrid, Spain.
Sandra
S
Martínez
Laura
L
Pérez
Carlos M
CM
Galmarini
Miguel
M
Aracil
Juan C
JC
Tercero
Federico
F
Gago
Beatriz
B
Albella
Juan A
JA
Bueren
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002243:Carbolines / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016685:Mitomycin / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000077606:Trabectedin
D000970:Antineoplastic Agents; D002243:Carbolines; D004149:Dioxoles; D051856:Fanconi Anemia Complementation Group Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; C500383:PM 00104; C568606:PM 01183; D044005:Tetrahydroisoquinolines; D016685:Mitomycin; D004247:DNA; D000077606:Trabectedin
DNA damage; DNA inter-strand cross-linking drugs; Fanconi anaemia; PM01183; Zalypsis; anti-cancer drugs; trabectedin