Sodium stibogluconate interacts with IL-2 in anti-Renca tumor action via a T cell-dependent mechanism in connection with induction of tumor-infiltrating macrophages.
IL-2 therapy results in 10-20% response rates in advanced renal cell carcinoma (RCC) via activating immune cells, in which the protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1) is a key negative regulator. Based on finding that sodium stibogluconate (SSG) inhibited SHP-1, the anti-RCC potential and action mechanism of SSG and SSG/IL-2 in combination were investigated in a murine renal cancer model (Renca). Despite its failure to inhibit Renca cell proliferation in cultures, SSG induced 61% growth inhibition of Renca tumors in BALB/c mice coincident with an increase (2-fold) in tumor-infiltrating macrophages (Mphi). A combination of SSG and IL-2 was more effective in inhibiting tumor growth (91%) and inducing tumor-infiltrating Mphi (4-fold), whereas IL-2 alone had little effect. Mphi increases were also detected in the spleens of mice treated with SSG (3-fold) or SSG/IL-2 in combination (6-fold), suggesting a systemic Mphi expansion similar to those in SHP-deficient mice. T cell involvement in the anti-Renca tumor action of the combination was suggested by the observations that the treatment induced spleen IFN-gamma T cells in BALB/c mice, but failed to inhibit Renca tumor growth in athymic nude mice and that SSG treatment of T cells in vitro increased production of IFN-gamma capable of activating tumoricidal Mphi. The SSG and SSG/IL-2 combination treatments were tolerated in the mice. These results together demonstrate an anti-Renca tumor activity of SSG that was enhanced in combination with IL-2 and functions via a T cell-dependent mechanism with increased IFN-gamma production and expansion/activation of Mphi. Our findings suggest that SSG might improve anti-RCC efficacy of IL-2 therapy by enhancing antitumor immunity.
Fan
Keke
K
Department of Cancer Biology, The Cleveland Clinic Foundation, OH 44195, USA.
Zhou
Ming
M
Pathak
Manas K
MK
Lindner
Daniel J
DJ
Altuntas
Cengiz Z
CZ
Tuohy
Vincent K
VK
Borden
Ernest C
EC
Yi
Taolin
T
D000818:Animals; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D007155:Immunologic Factors / Q000008:administration & dosage; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D004791:Enzyme Inhibitors; D007155:Immunologic Factors; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse; D000967:Antimony Sodium Gluconate