Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.60 (caspase-7)
 920 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that sangivamycin may find clinical utility as a novel anti-cancer agent targeting PEL.
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PMID:Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells. 2443 42

Selenium compounds such as methylseleninic acid (MSA) and sodium selenite (SS) have been widely evaluated as potential anti-cancer agents in the clinical setting. Primary effusion lymphoma (PEL) is a non-Hodgkin's B-cell lymphoma, associated with immunosuppressed individuals, such as post-transplant or AIDS patients. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of PEL and Kaposi's sarcoma. Here, we found that MSA and SS markedly inhibited the growth of PEL cells compared with KSHV-uninfected B cells. MSA and SS caused ER stress, inducing the unfolded protein response (UPR) pathway in PEL cells that resulted in pro-apoptotic UPR, and finally apoptosis. The expression of UPR-related molecules (GRP78 and GADD34) and pro-apoptotic UPR molecules (CHOP, Bim, or Puma) were augmented in PEL cells treated with MSA or SS. In addition, these compounds induced the activation of caspase-4, an ER stress specific caspase, as well as caspase-3,-7, and -9 in PEL cells. We confirmed that thapsigargin which is an inducer of ER stress, dramatically decreased the viability of PEL cells, compared with KSHV-uninfected Ramos cells. We also investigated whether MSA or SS caused oxidization of cellular proteins in PEL cells. MSA and SS increased the levels of oxidative proteins in PEL cells, and the anti-oxidant agent (N-acetyl-l-cysteine) restored cell viability and suppressed caspase-7 activation in PEL cells treated with MSA or SS. Finally, we confirmed that MSA and SS induced neither lytic replication nor viral production in PEL cells. Taken together, MSA and SS could serve as lead compounds for the development of novel and effective drugs against PEL without the risk of de novo KSHV production.
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PMID:Methylseleninic acid and sodium selenite induce severe ER stress and subsequent apoptosis through UPR activation in PEL cells. 2816 10