Co-Targeting ErbB Receptors and the PI3K/AKT Axis in Androgen-Independent Taxane-Sensitive and Taxane-Resistant Human Prostate Cancer Cells.

Using two representative models of androgen-independent prostate cancer (PCa), PC3 and DU145, and their respective paclitaxel- and docetaxel-resistant derivatives, we explored the anti-tumor activity of targeting the ErbB receptors and AKT using small-molecule kinase inhibitors. These cells manifest varying degrees of neuroendocrine differentiation characteristics and differ in their expression of functional PTEN. Although the specific downstream signaling events post the ErbB receptor and AKT co-targeting varied between the PC3- and DU145-lineage cells, synergistic anti-proliferative and enhanced pro-apoptotic responses occurred across the wild-type and the taxane-resistant cells, independent of their basal AKT activation state, their degree of paclitaxel- or docetaxel-resistance, or whether this resistance was mediated by the ATP Binding Cassette transport proteins. Dual targeting also led to enhanced anti-tumor responses in vivo, although there was pharmacodynamic discordance between the PCa cells in culture versus the tumor xenografts in terms of the relative activation and inhibition states of AKT and ERK under basal conditions and upon AKT and/or ErbB targeting. The consistent inhibition, particularly of AKT, occurred both in vitro and in vivo, independent of the underlying PTEN status. Thus, co-targeting AKT with ErbB, and possibly other partners, may be a useful strategy to explore further for potential therapeutic effect in advanced PCa.

Targeting IκB Kinase ß/NF-κB Signaling in Human Prostate Cancer by a Novel IκB Kinase ß Inhibitor CmpdA.

NF-κB plays an important role in many types of cancer, including prostate cancer, but the role of the upstream kinase of NF-κB, IKKß, in prostate cancer has neither been fully documented nor are there any effective IKKß inhibitors used in clinical settings. Here, we have shown that IKKß activity is mediated by multiple kinases including IKKα in human prostate cancer cell lines that express activated IKKß. IHC analysis (IHC) of human prostate cancer tissue microarrays (TMA) demonstrates that phosphorylation of IKKα/ß within its activation loop gradually increases in low to higher stage tumors as compared with normal tissue. The expression of cell proliferation and survival markers (Ki-67, Survivin) and epithelial-to-mesenchymal transition (EMT) markers (Slug, Snail), as well as cancer stem cell (CSC)-related transcription factors (Nanog, Sox2, Oct-4), also increase in parallel among the respective TMA samples analyzed. IKKß, but not NF-κB, is found to regulate Nanog, which, in turn, modulates the levels of Oct4, Sox2, Snail, and Slug, indicating an essential role of IKKß in regulating CSCs and EMT. The novel IKKß inhibitor CmpdA inhibits constitutively activated IKKß/NF-κB signaling, leading to induction of apoptosis and inhibition of proliferation, migration, and stemness in these cells. CmpdA also significantly inhibits tumor growth in xenografts without causing apparent in vivo toxicity. Furthermore, CmpdA and docetaxel act synergistically to inhibit proliferation of prostate cancer cells. These results indicate that IKKß plays a pivotal role in prostate cancer, and targeting IKKß, including in combination with docetaxel, may be a potentially useful strategy for treating advanced prostate cancer. Mol Cancer Ther; 15(7); 1504-14. ©2016 AACR.

Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells.

Modulating telomere dynamics may be a useful strategy for targeting prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of taxane-based treatments for prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive, and androgen-insensitive prostate cancer cells. Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with sodium meta-arsenite (KML001) (an agent undergoing early clinical trials), including combinations with paclitaxel and docetaxel, were evaluated in parental and drug-resistant cells. The studies were extended to androgen-sensitive LNCaP cells and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp)-dependent and non-Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4-1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not breast cancer resistance protein. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to KML001. Furthermore, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions. KML001 induced telomere erosion, decreased telomerase gene expression, and was highly synergistic with the taxanes in wild-type and drug-resistant DU145 cells. This synergism extended to androgen-sensitive and androgen-insensitive LNCaP cells under basal and androgen-deprived conditions. These studies demonstrate that KML001 plus docetaxel and KML001 plus paclitaxel represent highly synergistic drug combinations that should be explored further in the different disease states of prostate cancer.

Synthesis of a highly water-soluble derivative of amphotericin B with attenuated proinflammatory activity.

Amphotericin B (AmB), a well-known polyene antifungal agent, displays a marked tendency to self-associate and, as a consequence, exhibits very poor solubility in water. The therapeutic index of AmB is low and is associated with significant dose-related nephrotoxicity, as well as acute, infusion-related febrile reactions. Reports in the literature indicate that the toxicity of AmB may be related to the physical state of the drug. Reaction of AmB in dimethylformamide with bis(dimethylaminopropyl)carbodiimide yielded an unexpected N-alkylguanidine/N-acylurea bis-adduct of AmB which was highly water-soluble. The absorption spectrum of the AmB derivative in water indicated excellent monomerization, and the antifungal activities of reference AmB and its water-soluble derivative against Candida albicans were found to be virtually identical. Furthermore, the water-soluble adduct is significantly less active in engaging TLR4, which would suggest that the adduct may be less proinflammatory.