Apoptosis of human melanoma cells by a combination of lonidamine and radiation.
Human melanoma is the most aggressive form of human skin cancer, and is notoriously resistant to any current modalities of cancer therapy. Here we show that lonidamine (LND), a mitochondria-targeting non-conventional chemotherapeutic agent, markedly induced apoptosis in radioresistant human malignant melanoma C32TG cells. Either LND of up to 250 microM or X-ray irradiation of up to 15 Gy alone induced only a few percent of the apoptosis when administrated separately. When the two agents were combined, the apoptosis prominently increased to 29.3 %. The apoptotic cells thus induced by the combination treatment showed chromatin condensation, a depletion in DeltaPsim, and an activation of caspase-3. A pan-caspase inhibitor Z-Asp-CH(2)DCB completely suppressed the apoptosis. The combination treatment also decreased Bcl-2 and Bad-phosphorylation. These results indicate that the mitochondria pathway of apoptosis would devise a new radiotherapy strategy for treating malignant melanoma.
Miyato
Yasuyuki
Y
Heavy-Ion Radiobiology Research Group, National Institute of Radiological Sciences, Chiba, Japan.
Ando
Koichi
K
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays; D051025:bcl-Associated Death Protein
D000970:Antineoplastic Agents; C494819:BAD protein, human; D002352:Carrier Proteins; D007191:Indazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011838:Radiation-Sensitizing Agents; D016159:Tumor Suppressor Protein p53; D051025:bcl-Associated Death Protein; C016371:lonidamine