piperidines and Lymphoma--Primary-Effusion

The induction of DNA damage together with the interference with DNA repair represents a promising strategy in cancer treatment. Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. AZD2461/UCN-01 combination activated p53/p21 and downregulated c-Myc in these cells, leading to a reduced expression level of RAD51, molecule involved in DNA repair. The effect of AZD2461/UCN-01 on c-Myc and p53/p21 was inter-dependent and, besides impairing cell proliferation, contributed to the activation of the replicative cycle of KSHV, carried in a latent state in PEL cells. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma.

Topics: Cell Line; Cell Proliferation; Cells, Cultured; Checkpoint Kinase 1; DNA Damage; Herpesvirus 8, Human; Humans; Leukocytes, Mononuclear; Lymphoma, Primary Effusion; Phthalazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Staurosporine; Tumor Suppressor Protein p53; Virus Replication

Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients.

Topics: Adult; Animals; Apoptosis; Cell Cycle Checkpoints; Comet Assay; Crizotinib; DNA Damage; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Hepatocyte Growth Factor; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Immunoblotting; Immunocompromised Host; Lymphoma, Primary Effusion; Male; Mice; Mice, SCID; Middle Aged; Oligonucleotide Array Sequence Analysis; Piperidines; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Xenograft Model Antitumor Assays; Young Adult