The purpose of the study was to examine the molecular mechanisms by which
rottlerin inhibited growth of human pancreatic
tumors in Balb C nude mice, and
pancreatic cancer cells isolated from Kras(G12D) mice. AsPC-1 cells were injected subcutaneously into Balb c nude mice, and
tumor-bearing mice were treated with
rottlerin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of components of Akt, Notch, and Sonic Hedgehog (Shh) pathways were measured by the immunohistochemistry, Western blot analysis, and/or q-RT-PCR. The effects of
rottlerin on
pancreatic cancer cells isolated from Kras(G12D) mice were also examined.
Rottlerin-treated mice showed a significant inhibition in
tumor growth which was associated with suppression of cell proliferation, activation of capase-3 and cleavage of PARP.
Rottlerin inhibited the expression of Bcl-2,
cyclin D1, CDK2 and CDK6, and induced the expression of Bax in
tumor tissues compared to untreated control.
Rottlerin inhibited the markers of angiogenesis (Cox-2,
VEGF, VEGFR, and IL-8), and
metastasis (MMP-2 and MMP-9), thus blocking production of tumorigenic mediators in tumor microenvironment.
Rottlerin also inhibited epithelial-mesenchymal transition by up-regulating
E-cadherin and inhibiting the expression of Slug and Snail. Furthermore,
rottlerin treatment of xenografted
tumors or
pancreatic cancer cells isolated from Kras(G12D) mice showed a significant inhibition in Akt, Shh and Notch pathways compared to control groups. These data suggest that
rottlerin can inhibit
pancreatic cancer growth by suppressing multiple signaling pathways which are constitutively active in
pancreatic cancer. Taken together, our data show that the
rottlerin induces apoptosis and inhibits
pancreatic cancer growth by targeting Akt, Notch and Shh signaling pathways, and provide a new therapeutic approach with translational potential for humans.