3-(4-chlorophenyl)-adamantane-1-carboxylic-acid-(pyridin-4-ylmethyl)amide and Prostatic-Neoplasms

The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, that is, sphingosine kinase 1 and 2 (SK1 and SK2), important molecular targets for cancer drug development. ABC294640 is a first-in-class SK2 small-molecule inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer, and that sphingolipids affect signaling by both proteins, the therapeutic potential for using ABC294640 in the treatment of prostate cancer was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for prostate cancer growth and proliferation. Key findings validate that ABC294640 treatment of early-stage and advanced prostate cancer models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell-cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these pre-clinical findings support the hypotheses that SK2 activity is required for prostate cancer function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive prostate cancer.. Sphingosine kinase inhibition disrupts multiple oncogenic signaling pathways that are deregulated in prostate cancer.

Topics: Adamantane; Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Progression; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Pyridines; Receptors, Androgen; Signal Transduction; Small-Conductance Calcium-Activated Potassium Channels; Xenograft Model Antitumor Assays

Endogenous sphingolipid signaling has been shown to play an important role in prostate cancer endocrine resistance.. The novel SphK2 inhibitor, ABC294640, was used to explore SphK signaling in androgen resistant prostate cancer cell death signaling.. It dose-dependently decreased PC-3 and LNCaP cell viability, IC(50) of 28 ± 6.1 μM (p < 0.05) and 25 ± 4.0 μM (p < 0.05), respectively. ABC294640 was more potent in long-term clonogenic survival assays; IC(50) of 14 ± 0.4 μM (p < 0.05) in PC-3 cells and 12 ± 0.9 μM (p < 0.05) in LNCaP cells. Intrinsic apoptotic assays failed to demonstrate increased caspase-9 activity. Ki-67 staining demonstrated decreased proliferation by 50 ± 8.4% (p < 0.01) in PC-3 cells.. SphK2 inhibition decreases androgen resistant prostate cancer viability, survival, and proliferation independently of the intrinsic apoptotic pathway. Findings are in contrast to recent observations of ABC29460 acting dependently on the intrinsic pathway in other endocrine resistant cancer cell lines.

Topics: Adamantane; Androgen Antagonists; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Humans; Ki-67 Antigen; Male; Phosphotransferases (Alcohol Group Acceptor); Prostatic Neoplasms; Pyridines