Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study primarily describes the cytostatic activity of a bisphosphonate and of an alkylating agent linked bisphosphonate toward mammary carcinomas in vivo. Bisphosphonates had been shown to be therapeutically active in bone metastases. There is no animal tumor model available in which both primary mammary carcinomas and bone metastases can be studied simultaneously. Therefore, the Walker carcinosarcoma model, which was used as a model for bone metastasis in earlier studies, was combined with the M-methyl-N-nitrosourea (MNU) induced mammary carcinoma as a model for the primary tumor. Four-, or six-week treatment of MNU-induced mammary carcinomas in Sprague-Dawley rats with the new aromatic bisphosphonate 4[4-[bis(2-chloroethyl)-amino]-phenyl]-1-hydroxybutane-1, 1-bisphosphonate (BAD) showed higher antitumor activity than treatment with melphalan or with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) alone. BAD is the APD moiety covalently bound to a molecule derived from melphalan. A combination therapy with 11.75 mg/kg/day APD and 0.6 mg/kg/day melphalan showed the best therapeutic efficacy in this tumor model. In comparison to monotherapy with BAD, APD, or melphalan, a significantly higher rate of complete remissions was achieved. APD, itself, was not genotoxic in 3 employed short term assays. Since bisphosphonates had been shown to be therapeutically active in bone metastases, the antitumor potency of these compounds against experimental primary mammary carcinomas, coupled with the non-genotoxicity of APD and the inhibition of osteolytic bone metastases, might be an important advancement for adjuvant chemotherapy of human mammary carcinomas.
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PMID:Anticancer activity of bisphosphonic acids in methylnitrosourea-induced mammary carcinoma of the rat--benefit of combining bisphosphonates with cytostatic agents. 305 67

GCS-100 is a galectin-3 antagonist with an acceptable human safety profile that has been demonstrated to have an antimyeloma effect in the context of bortezomib resistance. In the present study, the mechanisms of action of GCS-100 are elucidated in myeloma cell lines and primary tumor cells. GCS-100 induced inhibition of proliferation, accumulation of cells in sub-G(1) and G(1) phases, and apoptosis with activation of both caspase-8 and -9 pathways. Dose- and time-dependent decreases in MCL-1 and BCL-X(L) levels also occurred, accompanied by a rapid induction of NOXA protein, whereas BCL-2, BAX, BAK, BIM, BAD, BID, and PUMA remained unchanged. The cell-cycle inhibitor p21(Cip1) was up-regulated by GCS-100, whereas the procycling proteins CYCLIN E2, CYCLIN D2, and CDK6 were all reduced. Reduction in signal transduction was associated with lower levels of activated IkappaBalpha, IkappaB kinase, and AKT as well as lack of IkappaBalpha and AKT activation after appropriate cytokine stimulation (insulin-like growth factor-1, tumor necrosis factor-alpha). Primary myeloma cells showed a direct reduction in proliferation and viability. These data demonstrate that the novel therapeutic molecule, GCS-100, is a potent modifier of myeloma cell biology targeting apoptosis, cell cycle, and intracellular signaling and has potential for myeloma therapy.
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PMID:GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. 2019 Jan 89

Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinum-resistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Resensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage-mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.
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PMID:DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance. 2213 82

Glioblastoma multiforme (GBM) is the most common and devastating form of primary central nervous system malignancy. The prognosis for patients diagnosed with GBM is poor, having a median survival rate of 12-15 months. Despite modern advances in the development of antineoplastic agents, the efficacy of newer anti-cancer agents in the treatment of GBM is yet to be determined. Thus, there remains a significant unmet need for new therapeutic strategies against GBM. A promising chemotherapeutic intervention has emerged from studies of cannabinoid receptor agonists wherein tetrahydrocannabinol has been the most extensively studied. The novel cannabinoid ligand KM-233 was developed as a lead platform for future optimization of biopharmaceutical properties of classical based cannabinoid ligands. Treatment of U87MG human GBM cells with KM-233 caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K. Almost complete mitochondrial depolarization was observed 6 h post-treatment followed by a rapid increase in cleaved caspase 3 and significant cytoskeletal contractions. Treatment with KM-233 also resulted in a redistribution of the Golgi-endoplasmic reticulum structures. Dose escalation studies in the orthotopic model using U87MG cells revealed an 80 % reduction in tumor size after 12 mg/kg daily dosing for 20 days. The evaluation of KM-233 against primary tumor tissue in the side flank model revealed a significant decrease in the rate of tumor growth. These findings indicate that structural refinement of KM-233 to improve its biopharmaceutical properties may lead to a novel and efficacious treatment for GBM.
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PMID:Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233. 2287 10