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NK-mediated reduction of malignancy in human melanoma cells treated with theophylline
I Gitelman1, W Abramow-Newerly, J C Roder
1Department of Immunology, University of Toronto, Canada.
Abstract:
Theophylline-treated cells of the human melanoma line showed an increase in NK-sensitivity in vitro and a concomitant decrease in tumorigenicity and spontaneous metastasis in Balb/c nude mice. The MeWo cells were heterogeneous and contained related subpopulations which were cloned to produce two cell lines, one hypodiploid (Cd-16) and one hypotetraploid (Ct-1). Prolonged (3 months) or short-term (4 days) treatment of these cell lines with 1 mM theophylline markedly reduced the incidence and size of tumors in Balb/c nude mice early after s.c. injection and their ability to metastasize spontaneously to the lung was also reduced. The effect was much more pronounced with Cd-16 cells, which contain amplified DNA compared to Ct-1 cells which lack DNA amplification. Part of the tumor inhibition caused by theophylline was due to natural killer (NK) cells. Thus, in vivo treatment of nude mice with anti-asialo GM1, a procedure known to remove NK cells, partially reversed the inhibitory effects of theophylline on tumor formation and generation of metastasis by Cd-16 cells. Consistent with this observation theophylline treatment enhanced the in vitro NK sensitivity of Cd-16 cells four-fold whereas Ct-1 was enhanced only slightly. The data suggest that theophylline can act preferentially on certain tumor cell subpopulations to enhance their NK-sensitive phenotype and thereby inhibit their capacity to form tumors and to metastasize in nude mice.
Insights
Theophylline treatment enhances natural killer (NK) cell sensitivity in melanoma cells, reducing tumor growth and metastasis in mice. This effect is more significant in specific DNA-amplified cell subpopulations.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Human melanoma cell lines exhibit heterogeneity.
- Tumorigenicity and metastatic potential vary among melanoma subpopulations.
Purpose of the Study:
- To investigate the effect of theophylline on melanoma cell sensitivity to natural killer (NK) cells.
- To evaluate theophylline's impact on melanoma tumor formation and metastasis in vivo.
Main Methods:
- Cloning of heterogeneous MeWo melanoma cells into hypodiploid (Cd-16) and hypotetraploid (Ct-1) lines.
- In vitro and in vivo treatment with theophylline (1 mM).
- Assessment of tumor incidence, size, and spontaneous lung metastasis in Balb/c nude mice.
- In vivo NK cell depletion using anti-asialo GM1 antibody.
Main Results:
- Theophylline treatment reduced tumor incidence, size, and lung metastasis in mice.
- Theophylline significantly enhanced NK-cell sensitivity in Cd-16 cells compared to Ct-1 cells.
- NK cell depletion partially reversed the anti-tumor and anti-metastatic effects of theophylline.
Conclusions:
- Theophylline preferentially enhances NK-cell sensitivity in specific melanoma subpopulations.
- Theophylline inhibits melanoma tumor formation and metastasis, partly through NK cell-mediated mechanisms.
- Targeting NK-sensitive melanoma subpopulations with theophylline shows therapeutic potential.