Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model.
Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor closely linked to chemoresistance in multiple myeloma cells. Whether curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with multiple myeloma, was investigated in vitro and in xenograft model in nude mice. Our results show that curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by down-regulating the constitutive activation of NF-kappaB and Akt, and this correlated with the suppression of NF-kappaB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and vascular endothelial growth factor. Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P<0.001, vehicle versus bortezomib+curcumin; P<0.001, bortezomib versus bortezomib+curcumin), and this correlated with suppression of Ki-67 (P<0.001 versus control), CD31 (P<0.001 versus vehicle), and vascular endothelial growth factor (P<0.001 versus vehicle) expression. Collectively, our results suggest that curcumin overcomes chemoresistance and sensitizes multiple myeloma cells to thalidomide and bortezomib by down-regulating NF-kappaB and NF-kappaB-regulated gene products.
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 143, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Bokyung
B
Sung
Ajaikumar B
AB
Kunnumakkara
Gautam
G
Sethi
Preetha
P
Anand
Sushovan
S
Guha
Bharat B
BB
Aggarwal
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000008:administration & dosage; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage; D015398:Signal Transduction; D013792:Thalidomide / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin