Sulfasalazine is commonly used as an
anti inflammatory agent and is known as a potent inhibitor of
NF-kappaB. Some
pancreatic carcinomas are characterized by a constitutively elevated
NF-kappaB activity accounting for chemoresistance. To elucidate whether blockade of
NF-kappaB activity with
sulfasalazine is suitable for overcoming this chemoresistance in vivo, we employed a mouse model with subcutaneously xenotransplanted human Capan-1
pancreatic carcinoma cells. Fourteen days upon
tumor inoculation, animals were randomized in 6 groups, receiving no treatment, treatment with
gemcitabine or with
etoposide, either alone or in combination with
sulfasalazine, or with
sulfasalazine alone. Two
therapy regimens were given with a 7-day interval in between. Upon treatment with
etoposide or
gemcitabine alone,
tumor sizes were moderately reduced to 65-68% and 50-65%, respectively, as compared to untreated
tumors.
Sulfasalazine alone only decreased temporarily the
tumor sizes.
Sulfasalazine in combination with
gemcitabine showed only partially higher reduction in
tumor sizes than
gemcitabine alone, whereas the combination with
etoposide reduced significantly the
tumor sizes in all experiments (down to 20%). TUNEL-staining showed higher numbers of apoptotic cells in
tumors from the combination groups, in particular with
etoposide, and proliferation as indicated by Ki67 staining was strongly reduced. Furthermore, combined treatment of
sulfasalazine with the
cytostatic drugs led to a decreased blood vessel density. Immunohistochemical staining of the activated p65 subunit showed that
sulfasalazine treatment abolished the basal
NF-kappaB activity in
tumor xenografts. These data imply that the well established anti-inflammatory drug
sulfasalazine sensitizes
pancreatic carcinoma cells to anti
cancer drugs, in particular to
etoposide in vivo by inhibition of
NF-kappaB. This combined
chemotherapy offers great potential for improved anti-
tumor responses in
pancreatic carcinomas.