Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop.
Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.
C.A.I.R. Institute, Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel. srednib@mail.biu.ac.il
Benjamin
B
Sredni
Merav
M
Weil
Gennadi
G
Khomenok
Ilana
I
Lebenthal
Seagal
S
Teitz
Yael
Y
Mardor
Zvi
Z
Ram
Arie
A
Orenstein
Amir
A
Kershenovich
Shalom
S
Michowiz
Yan I
YI
Cohen
Zvi H
ZH
Rappaport
Ilya
I
Freidkin
Michael
M
Albeck
Dan L
DL
Longo
Yona
Y
Kalechman
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005030:Ethylenes / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005030:Ethylenes; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016753:Interleukin-10; C054105:ammonium trichloro(dioxoethylene-O,O'-)tellurate; D017239:Paclitaxel