Resveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-regulation of STAT3 and nuclear factor-κB–regulated antiapoptotic and cell survival gene products in human multiple myeloma cells

Abstract

IntroductionMultiple myeloma (MM) or plasma cell myeloma is characterized by latent accumulation of secretory plasma cells with a low proliferative index and an extended life span in the bone marrow. 1 The second most prevalent hematologic cancer after non-Hodgkin lymphoma, multiple myeloma accounts for 10% of all hematologic cancers and approximately 2% of all cancer deaths. Conventional therapy for multiple myeloma involves combinations of vincristine, carmustine (bischloroethylnitrosourea), melphalan, cyclophosphamide, doxorubicin (Adriamycin), and prednisone or dexamethasone. 2 Patients younger than 65 years are usually given high-dose melphalan with autologous stem cell support, and older patients or those who cannot tolerate such intensive treatment are given standard-dose oral melphalan and dexamethasone. Shortcomings of these treatments are low remission rates (about 5%), short survival times (median, 30-36 months), and the development of drug resistance. 3,4 Chemoresistance remains a major therapeutic challenge in MM. The precise mechanism underlying chemoresistance in multiple myeloma is not clear, but one of the main contributors to both chemoresistance and pathogenesis is thought to be activation of NF-B and STAT3 and dysregulation of apoptosis. [4][5][6][7][8] Overexpression of antiapoptotic molecules has been linked to chemoresistance in MM; in one study, expression of the antiapoptotic protein Bcl-xL correlated with chemoresistance, with chemoresponse rates of 83% to 87% among non-Bcl-xL-expressing cases but only 20% to 31% among Bcl-xL-expressing cases. 9 Chemoresistance in several types of cancer has been linked to activation of NF-B, a transcription factor with central roles in the regulation of cell growth, survival, angiogenesis, cell adhesion, and apoptosis. 10 Progression and chemoresistance are also thought to involve interleukin 6 (IL-6), expression of which is induced by NF-B, through its regulation of the growth and survival of tumor cells. 11,12 IL-6 leads to constitutive activation of STAT3, which in turn results in expression of high levels of Bcl-xL. 6 Bcl-2 overexpression, another important characteristic of many multiple myeloma cell lines, 13 can rescue cells from glucocorticoid-induced apoptosis. 4 Cell lines resistant to doxorubicin (eg, RPMI 8226-Dox-40) have been shown to overexpress Bcl-xL. 9 Thus, both constitutive activation of NF-B and STAT3 play an important role in chemoresistance, and inhibition of NF-B and STAT3 may overcome this chemoresistance.The use of natural agents may be able to overcome resistance without some of the debilitating side effects of conventional chemotherapy. One such agent is resveratrol, a polyphenol (trans-3, The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on March 22, 2019. by guest www.bloodjournal.org From 4Ј, 5-trihydroxystilbene) abundant in red grape...

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression

“…1 and 3). However, RSV has many additional targets within the cell, including general modulators of transcription Sirtuins (class III histon deacetylases) [48,49], transcription factors NF-κB and STAT3 [16,17] and many enzymes of general cell metabolism [46]. RSV treatment of several melanoma lines induced a relatively modest decrease in the high basal NF-κB activity and NF-κB-dependent transcription in these cells, while downregulation of STAT3 levels and STAT3-dependent transcription was more pronounced (Fig.…”

“…Apart from protein synthesis inhibitors, RSV was previously implicated in sensitization to TRAIL-mediated apoptosis in different cancer cell lines [16,17,35]. Based on its effects on signaling pathways and expression of anti-apoptotic proteins (Fig.…”

“…Resveratrol (RSV) was previously shown to suppress JAK2-STAT3, Src-STAT3 and IKK-NF-κB activation and to induce apoptosis in some cancer cell lines [16][17][18]. We have demonstrated that, as with sodium arsenite, RSV suppressed expression of antiapoptotic cFLIP protein in human melanomas and dramatically increased sensitivity to exogenous TRAIL in TRAIL-R2/DR5-positive melanomas.…”

Akt associates with nuclear factor κB and plays an important role in chemoresistance of gastric cancer cells

“…Therefore, the efficacy of chemotherapeutics is severely limited because of chemoresistance. Several studies have suggested that the serine-threonine kinase Akt and the transcription factor NF-κB, are the key molecules for protecting cells from undergoing apoptosis, and that the Akt and NF-κB mediated survival signaling pathway is associated with chemoresistance of human tumors (1)(2)(3).…”

“…PIP2 and PIP3 bind to the PH domain of Akt, resulting in translocation of Akt to the plasma membrane area (4,5). Akt has been reported to be a signal transduction protein that figures prominently in the mechanisms of carcinogenesis and chemoresistance (3,6,7).…”