Interleukin-6 (IL-6) is a multifunctional
cytokine that is produced not only by a variety of normal cells but also by
cancer cells.
IL-6 produced by
cancer cells stimulates the proliferation of these
cancer cells in an autocrine/ paracrine manner and causes
paraneoplastic syndromes including
hypercalcemia,
cachexia, and
leukocytosis. We have reported previously that a human oral squamous
cancer associated with
hypercalcemia produces large amounts of
IL-6, that animals bearing this
cancer exhibit elevated levels of plasma
IL-6, and that
neutralizing antibodies to human
IL-6 reverse
hypercalcemia in
tumor-bearing animals, indicating an important role of
IL-6 in the
hypercalcemia in this model. Because these
cancer cells overexpress
epidermal growth factor receptors (EGFR) with intrinsic
tyrosine kinase (TK) activity similar to many other squamous
cancers, we examined the effects of
herbimycin A, a
tyrosine kinase inhibitor, on
IL-6 production and
hypercalcemia in animals bearing this
cancer to develop a new approach to treat the
hypercalcemia associated with
malignancy. Intraperitoneal administration (once a day for 2 days) of
herbimycin A to
cancer-bearing hypercalcemic mice reduced the plasma levels of human
IL-6 and impaired the
hypercalcemia. During 2-day treatment with
herbimycin A, no changes were observed in
tumor size. Of interest, plasma levels of mouse, but not human, soluble
IL-6 receptors were also elevated. However,
herbimycin A showed no effects on plasma levels of mouse soluble
IL-6 receptors.
Herbimycin A suppressed the
tyrosine autophosphorylation of EGFR and
IL-6 mRNA expression and production, all of which were stimulated by
EGF. The data raise the possibility that TK inhibitors may be potential mechanism-based therapeutic agents for the treatment of
hypercalcemia associated with squamous
cancers which overexpress EGFR.