Chemosensitizing effect of nordihydroguaiaretic acid and its tetra-acetylated derivative on parental and multiresistant TA3 mouse mammary adenocarcinoma cells.
BACKGROUND
Multidrug resistance (MDR) continues being the major obstacle for successful anticancer chemotherapy.


METHODS
The action of nordihydroguaiaretic acid (NDGA) and its tetra-acetylated derivative (NDGATA) on TA3 mouse mammary adenocarcinoma cells and their ability to restore doxorubicin (DOX), cisplatin (CPT) and methotrexate (MTX) sensitivity of the multiresistant variant TA3-MTX-R was examined.


RESULTS
Both NDGA and NDGATA synergistically enhanced the cytotoxicity of DOX, CPT and MTX, with a more evident effect in the TA3-MTX-R than in the TA3 cells. NDGATA was more effective than NDGA, as analyzed by the isobologram method. The combination of NDGATA and DOX also reduced the tumor growth rate in mice. Although it did not prolong the median survival time, 30% of mice showed no vestiges of tumor 200 days after implantation with either TA3 or TA3-MTX-R cells. Moreover, NDGA and NDGATA increased the accumulation of DOX and rhodamine (RHO) 123 in both cell lines.


CONCLUSIONS
NDGA and NDGATA are able to chemosensitize tumor cells and combination therapy with NDGATA and DOX is effective at inhibiting tumor growth in mice.
Plaza
Claudio
C
Programa de Farmacología Molecular y Clínica, ICBM, Facultad de Medicina, Universidad de Chile, Casilla, Santiago, Chile.
Pavani
Mario
M
Araya-Maturana
Ramiro
R
Pezoa
Jaqueline
J
Maya
Juan Diego
JD
Morello
Antonio
A
Becker
Maria Inés
MI
DE Ioannes
Alfredo
A
Ferreira
Jorge
J
D000107:Acetylation; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D008136:Longevity / Q000187:drug effects; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009637:Masoprocol / Q000737:chemistry / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D020112:Rhodamine 123 / Q000378:metabolism
D000970:Antineoplastic Agents; D020112:Rhodamine 123; D009637:Masoprocol; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate