Inhibition of the tumour necrosis factor-alpha autocrine loop enhances the sensitivity of multiple myeloma cells to anticancer drugs.
Several autocrine soluble factors, including macrophage inflammatory protein-1α and tumour necrosis factor-alpha (TNF-α), promote the survival and growth of multiple myeloma (MM) cells. We hypothesised that inhibition of the TNF-α autocrine loop may enhance the cytotoxic effect of anticancer drugs in MM cell lines. In the present study, a TNF-α-neutralizing antibody suppressed cell proliferation and enhanced the cytotoxic effect of anticancer drugs on MM cells. In addition, combination treatment with the TNF-α-neutralizing antibody and the chemotherapy agent melphalan inhibited nuclear factor κB (NF-κB) p65 nuclear translocation and mammalian target of rapamycin (mTOR) activation and upregulated the expression of Bax and Bim. Treatment of ARH-77 cells with the NF-κB inhibitor dimethyl fumarate or the mTOR inhibitor rapamycin suppressed NF-κB p65 nuclear translocation and enhanced the cytotoxic effect of melphalan. Furthermore, infliximab, a monoclonal antibody against TNF-α, also enhanced the cytotoxic effect of anticancer drugs in ARH-77 cells. These results indicated that TNF-α-neutralizing antibodies or infliximab enhanced the cytotoxic effect of anticancer drugs by suppressing the TNF receptor/mTOR/NF-κB pathways. The inhibition of TNF-α may thus provide a new therapeutic approach to control tumour progression and bone destruction in MM patients.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Masanobu
M
Tsubaki
Makiko
M
Komai
Tatsuki
T
Itoh
Motohiro
M
Imano
Kotaro
K
Sakamoto
Hirotaka
H
Shimaoka
Naoki
N
Ogawa
Kenji
K
Mashimo
Daichiro
D
Fujiwara
Tomoya
T
Takeda
Junji
J
Mukai
Katsuhiko
K
Sakaguchi
Takao
T
Satou
Shozo
S
Nishida
D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019898:Autocrine Communication / Q000187:drug effects; D000069462:Dimethyl Fumarate; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005650:Fumarates / Q000494:pharmacology* / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000069285:Infliximab; D008558:Melphalan / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D005650:Fumarates; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000069462:Dimethyl Fumarate; D008558:Melphalan
Multiple myeloma; NF-κB; TNF-α; mTOR