Growth inhibition, nuclear uptake, and retention of anthracycline-formaldehyde conjugates in prostate cancer cells relative to clinical anthracyclines.
Recent data indicate that the clinical anthracycline anti-tumor drugs, doxorubicin (DOX), daunorubicin (DAU), and epidoxorubicin (EPI), catalyze the production of formaldehyde through induction of oxidative stress and bind the formaldehyde to form a metabolite which covalently bonds to DNA. Based upon this discovery, anthracycline-formaldehyde conjugates were synthesized and evaluated in three metastatic prostate cancer cell lines, LNCaP, PC-3, and DU-145. The doxorubicin-formaldehyde conjugate, Doxoform (DOXF), inhibits the growth of PC-3 and DU-145 cells 50- and 80-fold better, respectively, than the corresponding clinical drug, DOX. Daunorubicin- and epidoxorubicin-formaldehyde conjugates, Daunoform and Epidoxoform (DAUF and EPIF), inhibit the growth about 6 to 10-fold better than the clinical drugs, DAU and EPI. In addition, DAUF, DOXF, and EPIF are 2- to 20-fold more toxic to the doxorubicin-sensitive metastatic prostate cancer cell line, LNCaP. Fluorescence microscopy indicates that the nucleus is the major target for all six drugs. Flow cytometry together with fluorescence microscopy shows that DOXF and EPIF are taken up more rapidly and more abundantly and are retained in the nucleus longer than DOX and EPI, respectively, especially in DU-145 cells. The enhanced toxicity of the anthracycline-formaldehyde conjugates is attributed to their increased nuclear uptake and retention and suggests that DOXF, DAUF, and EPIF are prodrugs to the active metabolites of the clinical drugs DOX, DAU, and EPI.
Taatjes
D J
DJ
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215, USA.
Koch
T H
TH
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism*; D004337:Drug Carriers; D005434:Flow Cytometry; D005557:Formaldehyde / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004337:Drug Carriers; D005557:Formaldehyde