midostaurin and Body-Weight

Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy with proteinuria and peritubular extracellular matrix production. We have previously shown that the PKC isoforms α and β mediate different cellular effects. PKC-β contributes to hyperglycemia-induced renal matrix production, whereby PKC-α is involved in the development of albuminuria. We further tested this hypothesis by deletion of both isoforms and used a PKC inhibitor. We analyzed the phenotype of nondiabetic and streptozotocin (STZ)-induced diabetic homozygous PKC-α/β double-knockout mice (PKC-α/β(-/-)). After 8 weeks of diabetes mellitus, the high-glucose-induced renal and glomerular hypertrophy as well as transforming growth factor-β1) and extracellular matrix production were diminished in the PKC-α/β(-/-) mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC-α/β(-/-) mice. Treatment with CGP41252, which inhibits PKC-α and PKC-β, is able to prevent the development of albuminuria and to reduce existing albuminuria in type 1 (STZ model) or type 2 (db/db model) diabetic mice. These results support our hypothesis that PKC-α and PKC-β contribute to the pathogenesis of diabetic nephropathy, and that dual inhibition of the classical PKC isoforms is a suitable therapeutic strategy in the prevention and treatment of diabetic nephropathy.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Isoenzymes; Kidney; Male; Mice; Mice, Knockout; Organ Size; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-alpha; Staurosporine

N-benzoyl-staurosporine (PKC412) is a selective inhibitor of protein kinase C, and it inhibits the growth of human cancer cells. In this study, we examined the antitumor effect of PKC412, given singly and in combination with paclitaxel, on tumor regression and chemotherapeutic side effects by assessing tumor burden and cytokine production responses in vivo. Twenty-six nude mice intraperitoneally inoculated with SKOV3 cells were treated differently in 4 treatment groups: PKC412 plus paclitaxel (n = 7), paclitaxel-only (n = 6), PKC412-only (n = 6), and controls (n = 7). At autopsy, we found that PKC412 itself slightly reduced the mass of tumor but did not fully inhibit tumor formation. The incidence of evident disease was decreased when PKC412 was combined with paclitaxel (43%). From the body weight of the tumor-bearing mice, we observed that PKC412 plus paclitaxel treated mice were less wasted than paclitaxel-only treated mice (18.1 g vs 22.4 g, p = 0.001). We measured intracellular TNFalpha, IFNgamma, IL-4, and IL-10 in stimulated mouse splenocytes using flow cytometry to determine if PKC412 inhibited cytokine production in T cells. TNFalpha, IFNgamma, and IL-10 production were all significantly inhibited in the paclitaxel-treated mice. The inhibitory effects on cytokine production by paclitaxel were compensated with PKC412 combination (p = 0.008, 0.035, 0.014, respectively). From this study, we deduce that PKC412 may have clinical applications in promoting tumor regression in ovarian cancer when combined with paclitaxel. Moreover, PKC412 is able to prevent weight loss and immunosuppression induced by paclitaxel because it rescues normal proliferating cells from cytotoxic effects.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Cytokines; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Protein Kinase C; Spleen; Staurosporine; Xenograft Model Antitumor Assays