Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells.
The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio-4-[(4'-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4'-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.
Uckun
Fatih M
FM
Department of Oncology, Drug Discovery Program, Parker Hughes Cancer Center & Parker Hughes Institute, St. Paul, MN, USA. fatih_uckun@ih.org
D'Cruz
Osmond J
OJ
Liu
Xing-Ping
XP
Narla
Rama Krishna
RK
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001152:Arsenicals / Q000138:chemical synthesis / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D008297:Male; D018613:Microscopy, Confocal; D009101:Multiple Myeloma / Q000517:prevention & control; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000517:prevention & control; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013736:Testicular Neoplasms / Q000517:prevention & control; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; C020979:benzenearsonic acid