Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling pathways for caspase-2-mediated apoptosis are poorly defined. This is partially due to a lack of a reproducible stimulus to trigger caspase-2 activation. We present the oligonucleotide Dz13, a DNA enzyme that cleaves c-Jun mRNA and is capable of inhibiting various model tumors in mice, which potently induces caspase-2 resulting in apoptosis in a panel of tumor cell lines. Dz13-mediated cell death occurred even in the absence of known caspase-2 molecular partners in p53-induced protein with a death domain, RIP-associated Ich-1/CED homologous protein with death domain, or DNA-dependent protein kinase catalytic subunit, or other caspases in cell lines of breast cancer, prostate cancer, osteosarcoma, and liposarcoma. z-VDVAD-fmk, caspase-2(-/-) mouse embryonic fibroblasts and siRNA silencing of caspase-2 in tumor cells abrogated Dz13-mediated cell death. In an orthotopic tumor model, expression of caspase-2 increased as the tumor metastasized and caspase-2 expression was sporadic in patient tumor specimens. These findings provide hope that Dz13, and other agents that evoke activation of caspase-2, may be therapeutic clinically.
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PMID:Dz13, a c-jun DNAzyme, is a potent inducer of caspase-2 activation. 2018 Jun 31

The oligonucleotide Dz13 is a DNA enzyme (deoxyribozyme) that cleaves c-Jun mRNA. It has efficacious effects against tumors directly, is active against tumor-induced angiogenesis, inhibits neointima formation after arterial injury, and controls inflammatory responses. The off-target effects of Dz13 may in fact be driving some of these potentially therapeutic effects, though no mechanisms have been clearly defined in target cells. To this end, we here show that when a panel of human tumor cells that naturally propagate in bone are challenged with Dz13, the tumor suppressor E2F1 is upregulated regardless of cellular p53 status. The piddosomal components, p53-induced protein with a death domain and caspase-2, were translocated to the nucleus when deoxyribozymes were incubated with cells, but RIP associated Ich-1/CED homologous protein with death domain levels increased throughout the cell with either Dz13 or its scrambled control oligonucleotide. In response to Dz13-mediated cytotoxicity, cells upregulated levels of ERK, Akt, and p38. Summarily, these results suggest a cytotoxic stress (resembling DNA damage) response of tumor cells to Dz13, which induces apoptosis via the activation of inhibitor of caspase-activated deoxyribonuclease and protein kinase C delta. In vivo, in tumor-in-bone orthotopic and clinically relevant models for prostate and breast cancer metastasis, and a novel spontaneously metastasizing model for osteosarcoma (OS), Dz13 decreased growth in bone, and also metastasis for OS. This new model for OS was assessed to be clinically relevant in its expression of typical bone markers, osteopontin and osteocalcin. These results provide an off-target mechanism for Dz13 function, but this may be useful therapeutically against tumors.
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PMID:Dz13 induces a cytotoxic stress response with upregulation of E2F1 in tumor cells metastasizing to or from bone. 2040 96

Osteosarcomas (OSs) are characterized by high levels of genomic instability (GI). To gain insights into the GI and its contribution toward understanding the genetic basis of OS, we characterized 19 primary and 13 metastatic mouse tumors in a genetically engineered novel mouse model of OS by a combination of genomic techniques. Through the bone-specific deletion of the wild-type Trp53 locus or activation of a metastatic-promoting missense R172Hp53 allele, C57BL/6 mice developed either localized or metastatic OS. Subsequent tumors were isolated and primary cultures created from primary bone and/or distal metastatic lesions, for example, lung and liver. These tumors exhibited high levels of GI with complex chromosomal rearrangements, amplifications, and deletions comparable to human OS. The combined genomic approaches identified frequent amplification of chromosome 15D1 and loss of 11B4 by CGH and/or SKY. Both 15D1 and 11B4 have homology with frequently altered chromosomal bands 8q24 and 17p13 in human OS, respectively. Subsequent array CGH, FISH, and qRT-PCR analysis identified coamplification and overexpression of Myc/Pvt1 transcripts from the 15D1 amplicon and loss and decreased expression of the Nlrp1b from 11B4. The Nlrp1 gene is the key mediator of apoptosis and interacts strongly with caspase 2.
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PMID:Coamplification of Myc/Pvt1 and homozygous deletion of Nlrp1 locus are frequent genetics changes in mouse osteosarcoma. 2635 45

It has been historically uncertain if extra centrosomes are a cause or consequence of tumorigenesis. Experiments have recently established that overexpression of polo-like kinase 4 (PLK4) promotes centrosome amplification with consequential promotion of cellular aneuploidy. Furthermore, centrosome amplification drives spontaneous tumorigenesis in mice. Tissues lacking normal functional p53 tolerate extra centrosomes, whereas p53 proficient tissues initiate proliferative arrest in this circumstance. Extra centrosomes trigger activation of the multi-protein PIDDosome complex, with Caspase-2 effecting cleavage of the p53-negative regulator mouse double minute 2, consequent stabilization of p53 and p21-dependent arrest of the cell cycle. The co-occurrence of cellular aneuploidy, complex chromosomal rearrangements and p53 dysfunction is a striking feature of some osteosarcomas. It is postulated that small-molecule PLK4 inhibitors such as CFI-400945, which are in development, may have utility in osteosarcoma given these findings.
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PMID:Targeting the centrosome and polo-like kinase 4 in osteosarcoma. 3050 38

Pigment epithelium-derived factor (PEDF) is known for its osteogenic properties, but its effects against primary and secondary bone tumors have not comprehensively been demonstrated. We show the ubiquitous expression of PEDF in murine embryonic tissue. Continuous administration of PEDF in pregnant mice for five days did not adversely affect foetal health, despite PEDF's known potent antiangiogenic properties. In the case of the devastating childhood bone cancer osteosarcoma, PEDF has direct anticancer activity per se, and protects against the toxicity of doxorubicin in the heart, small intestine and testes. PEDF demonstrated anti-proliferative and pro-apoptotic effects against human prostate and breast cancer cells, tumors which are known to metastasize to bone as the preferred secondary site. Caspase-2 was activated in both tumor cell types by PEDF. In models of prostate and breast cancer in bone, PEDF significantly reduced tumor volumes. When combined with zoledronic acid, continuously-administered PEDF significantly reduced breast tumor volume at the bone, and was able to preserve the quality of bone better than the combination therapy. These multiple positive findings make PEDF an ideal endogenous and safe biological for possible future clinical testing.
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PMID:Triple-threat activity of PEDF in bone tumors: Tumor inhibition, tissue preservation and cardioprotection against doxorubicin. 3102 61