Triptolide overcomes dexamethasone resistance and enhanced PS-341-induced apoptosis via PI3k/Akt/NF-kappaB pathways in human multiple myeloma cells.
Human multiple myeloma is a presently incurable hematological malignancy and novel biologically based therapies are urgently needed. Triptolide (TPL) is a purified diterpenod isolated from the Chinese herb, Tripterygium wilfordii Hook. F that has shown antitumor activities in various cancer cell types. But its activity in Dex-resistant multiple myeloma cell lines and the main upstream signaling pathway has not been reported. Here we show that TPL induces apoptosis in dexamethasone-sensitive (MM.1S) and dexamethasone-resistant (MM.1R) cells, most importantly its main upstream signaling pathway is through the PI3k/Akt/NF-kappaB pathway and is also associated with MAPK pathway, via mitochondrial apoptotic signaling and is also associated with the caspase and Bcl-2 family members. Moreover, TPL was able to enhance the activities of dexamethasone or bortezomib/PS-341 in multiple myeloma cell lines. Collectively, these findings provide the framework for a clinical evaluation of TPL, either alone or in combination with dexamethasone or bortezomib/PS-341, to overcome drug resistance and improve outcome for patients with this universally fatal hematological malignancy.
Yang
Min
M
Department of Hematology, Zhejiang University, Hangzhou 310003, People's Republic of China.
Huang
Jian
J
Pan
Han-Zhang
HZ
Jin
Jie
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D010616:Phenanthrenes / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004224:Diterpenes; D004852:Epoxy Compounds; D020672:I-kappa B Proteins; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011965:Receptors, Glucocorticoid; C001899:triptolide; D000069286:Bortezomib; D003907:Dexamethasone; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt