Figure 3

Novel therapeutic strategies against aggressive, invasive and metastatic PC cancers by targeting distinct growth factor signaling cascades and drug resistance-associated molecules in prostatic cancer stem/progenitor cells and their progenies. The possible antiproliferative, antiinvasive and/or apoptotic effects induced by a specific inhibitor of tyrosine kinase activity of EGFR (gefitinib and erlotinib), receptor tyrosine kinase (RTK) activity, smoothened (SMO) hedgehog signaling element (cyclopamine and GDC-0449), Notch (γ-secretase inhibitor) and Wnt/β-catenin (sFRP2) as well as TGFβR antagonist or CXCR4 antagonist (AM3100) and monoclonal antibody (mAb) directed against SHH ligand, CD44, Wnt ligand or CXCR4 are indicated. Moreover, the inhibitory effect induced by different pharmacological agents on the downstream signaling effectors induced through these growth factor cascades and under hypoxic conditions such as PI3K/Akt/mTOR, NF-κB and HIFs as well as an inhibitor of glycolytic metabolism (2-DG) and 2-DG-induced autophagy (metformin) is also indicated. In addition, the potent inhibitory effect mediated by a specific inhibitor of EGFR or hedgehog on ABCG2-multidrug efflux pump and whose event may lead to the intracellular accumulation of chemotherapeutic drugs is also illustrated.