Abstract:
BACKGROUND:Inhibitors of heat shock protein (Hsp) 90 induce apoptosis in multiple myeloma (MM) cells, but the molecular mechanisms underlying this cytotoxic outcome are not clear. Here, we investigate the effect of IPI-504, a novel and highly soluble inhibitor of the Hsp90 ATPase activity, on the unfolded protein response (UPR) in MM cells. The UPR is a stress response pathway triggered by sensors located at the endoplasmic reticulum (ER) membrane whose function is to reduce an excessive accumulation of misfolded protein in the ER. During normal development of B-lymphocytes to antibody-producing plasma cells, a partial UPR has been described, where IREalpha and ATF-6 are stimulated, whereas the third sensor, PERK, is not induced. METHODS:Levels of the activated forms of the three main UPR sensors ATF-6, XBP-1 and PERK/eIF-2 were monitored in two different MM cells lines and one non-MM cell lines under various experimental conditions including incubation with increasing concentration of IPI-504. Also, MM cells were incubated with IPI-504 and several apoptosis markers were monitored. RESULTS:We show here that a partial UPR is constitutively activated in plasma cell-derived MM cells and that IPI-504 can potently inhibit this pathway. IPI-504 achieves this by inactivating the transcription factors XBP1 and ATF6. In addition, IPI-504 also blocks the tunicamycin-induced phosphorylation of eIF2 by PERK. Dose-response and time course experiments reveal that IPI-504's inhibitory effect on the UPR parallels its cytotoxic and pro-apoptotic effects on MM cells. CONCLUSION:The results presented here suggest that the IPI-504-induced apoptosis might be, in part, mediated by the inhibition of the partial UPR. Other malignancies that rely on intact and efficient UPR to survive could be considered as new indications for Hsp90 inhibitors.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Patterson J,Palombella VJ,Fritz C,Normant Edoi
10.1007/s00280-007-0546-0subject
Has Abstractpub_date
2008-05-01 00:00:00pages
923-32issue
6eissn
0344-5704issn
1432-0843journal_volume
61pub_type
杂志文章abstract:PURPOSE:Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-012-1839-5
更新日期:2012-06-01 00:00:00
abstract::Eighteen previously untreated patients with advanced unresectable or metastatic soft-tissue sarcomas (STS) and two patients with locally invasive thymoma were treated with a combination of adriamycin (ADM) 80 mg/m2 on day 1 and cis-platinum (DDP) 120 mg/m2 on day 1. The regimen was repeated at 4-weeks intervals. In ST...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00257118
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:Oxaliplatin and satraplatin demonstrate activity against cisplatin-resistant tumor cells. Although the two platinum analogs are structurally-related, oxaliplatin is more active. Therefore, studies focusing on protein expression profiling were undertaken to identify the molecular mechanism for the difference in ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-020-04085-1
更新日期:2020-06-01 00:00:00
abstract::Fifty-one patients with non-small cell lung cancer (NSCLC) were treated, during a phase II trial, with 4'demethylepipodophyllotoxin-beta-D-ethylidene glucoside (VP16-213). Forty-nine were evaluable for response, and of these two (4%) had partial responses lasting 5 and 6 months. Prior treatment with chemotherapy may h...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00254550
更新日期:1982-01-01 00:00:00
abstract:PURPOSE:Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine. METHODS:We enrolled postoperativ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-020-04087-z
更新日期:2020-06-01 00:00:00
abstract::Purified human leukocyte interferon produced by recombinant techniques (IFN-alpha A) was tested in vitro with chemotherapeutic drugs, vinblastine (VLB), vincristine (VCR), vindesine (VDS), vinzolidine (VZL), cis-platinum (PLAT), doxorubicin (DOXO), etoposide (VP-16), and melphalan (MEL). The activity of these agents a...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00255753
更新日期:1983-01-01 00:00:00
abstract::Trastuzumab has deeply and radically changed the course of HER2-positive breast cancer disease. The recent development of a subcutaneous (SC) formulation of trastuzumab is an important step towards improved patients' care. SC trastuzumab at a fixed dose of 600 mg administered every 3 weeks for about 5 min provides a v...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2289-4
更新日期:2013-12-01 00:00:00
abstract:OBJECTIVE:Docetaxel given orally as monotherapy results in low bioavailability of <10%. Previous studies have indicated that the intestinal efflux pump P-glycoprotein (P-gp) prevents uptake from the gut resulting in low systemic exposure to docetaxel. The purpose of this study was to determine the degree of enhancement...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1007/s00280-004-0864-4
更新日期:2005-01-01 00:00:00
abstract:PURPOSE:Some clinical studies on etoposide (Eto) have shown marked schedule dependency of the effect (starting at about 1 mg/l) and toxicity (over about 10 mg/l) whereas other studies have not confirmed these results. What are the conclusions we can draw from these inconsistent results when developing new low-dose (LD)...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-001-0418-y
更新日期:2002-04-01 00:00:00
abstract::In the 1981 cooperative soft-tissue sarcoma (CWS-81) study, a clear correlation between the degree of response to initial chemotherapy comprising vincristine, actinomycin D, cyclophosphamide, and Adriamycin (VACA) and the survival of patients with rhabdomyosarcoma was found. In the subsequent CWS-86 study, cyclophosph...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00253241
更新日期:1989-01-01 00:00:00
abstract::A group of folate analogs of the 10-deaza-aminopterin series, which were designed on the basis of the results of an intensive biochemical and pharmacokinetic program, have been examined in therapy experiments utilizing a group of murine tumor models. These new analogs were found to be markedly superior to methotrexate...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract:PURPOSE:To evaluate the feasibility, toxicity and efficacy of the combination of docetaxel and mitomycin C as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS:Thirty-eight patients with histologically confirmed, locally advanced or metastatic NSCLC were includ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-006-0198-5
更新日期:2006-10-01 00:00:00
abstract:PURPOSE:Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-014-2385-0
更新日期:2014-03-01 00:00:00
abstract:PURPOSE:Based on the preclinical evidence of topoisomerase I (Topo-1) upregulation by mitomycin C(MMC) and decreased NF-kappaB activation by celecoxib, we evaluated combinations of irinotecan/MMC and irinotecan/MMC/celecoxib in patients with advanced solid malignancies. PATIENTS-METHODS:Initially, patients received MM...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-008-0826-3
更新日期:2009-05-01 00:00:00
abstract:PURPOSE:Since the hypothesis that solid tumors cause angiogenesis by secreting pro-angiogenic factors was introduced, research on angiogenesis has proceeded continuously. Development of inhibitors targeting the angiogenic tyrosine kinases, to block downstream signal transduction pathways, has become an important approa...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,评审
doi:10.1007/s00280-016-2961-6
更新日期:2016-05-01 00:00:00
abstract:PURPOSE:The primary objective of this investigation was to compare the extent of brain distribution of the lactone and the carboxylate forms of camptothecin (CPT) and topotecan (TPT) in awake freely moving rats. METHODS:The plasma concentration-time profiles of the lactone and the carboxylate forms of CPT and TPT were...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s002800050908
更新日期:1999-01-01 00:00:00
abstract:PURPOSE:Although anthracycline is a key agent in breast cancer treatment, its use is associated with the risk of cardiotoxicity. Recently, the value of combination therapy with docetaxel and cyclophosphamide was reported. Because the characteristics of paclitaxel differ on weekly versus tri-weekly administration, such ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-009-1137-z
更新日期:2010-05-01 00:00:00
abstract:PURPOSE:To evaluate the efficacy and safety of preoperative radiotherapy with capecitabine and mitomycin C in patients with locally advanced rectal cancer. METHODS:A prospective, open-label, non-randomized, phase II study was performed on 49 patients with locally advanced rectal cancer. Preoperative radiotherapy was c...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,随机对照试验
doi:10.1007/s00280-010-1469-8
更新日期:2011-09-01 00:00:00
abstract:BACKGROUND:Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-009-1225-0
更新日期:2010-10-01 00:00:00
abstract:PURPOSE:The study investigated the effects of pemetrexed, gefitinib, and their combination on human colorectal cancer cells. METHODS:Six human colorectal cancer cells were exposed to pemetrexed, gefitinib, and their combination. Antitumor effects were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium br...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2251-5
更新日期:2013-10-01 00:00:00
abstract::When tumor cell density increases, the cytotoxic activity of certain anticancer agents, such as vincristine (VCR) and doxorubicin (DXR), progressively decreases. This phenomenon is termed the inoculum effect. Since VCR and DXR are less active in an acidic environment, we questioned whether the inoculum effects could h...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF00695987
更新日期:1992-01-01 00:00:00
abstract:PURPOSE:The combination of an mTOR inhibitor with 5-fluorouracil-based anticancer therapy is attractive because of preclinical evidence of synergy between these drugs. According to our phase I study, the combination of capecitabine and everolimus is safe and feasible, with potential activity in pancreatic cancer patien...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-015-2730-y
更新日期:2015-06-01 00:00:00
abstract:PURPOSE:This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. METHODS:Emerging pharmacokinetic ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章,多中心研究
doi:10.1007/s00280-017-3328-3
更新日期:2017-06-01 00:00:00
abstract::The radiosensitizing activity, acute toxicity, and pharmacokinetics of a new hypoxic cell radiosensitizer, potassium 2-nitroimidazole-1-acetohydroxamate (KIH-802), were compared with those of misonidazole (MISO) and etanidazole (SR-2508). The radiosensitizing activity of KIH-802 was slightly higher than that of MISO a...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/BF02897255
更新日期:1990-01-01 00:00:00
abstract:PURPOSE:This phase I study was undertaken to evaluate the safety and tolerability of prolonged infusional etoposide, and to evaluate its pharmacokinetic/pharmacodynamic profile in patients with advanced cancer. METHODS:A group of 17 patients received a 7-day infusion of etoposide (schedule A) every 21 days at doses fr...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/s002800050511
更新日期:1996-01-01 00:00:00
abstract:PURPOSE:Although cisplatin is the drug of choice in treating lung cancer patients, relapse and resistance is a common drawback to its clinical effectiveness. Based on cisplatin's reported ability to interfere with numerous cellular components, including mitochondria, we probed alterations in metabolism in cisplatin-res...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2366-8
更新日期:2014-02-01 00:00:00
abstract::Chronic myeloid leukaemia (CML) is an unusual malignancy in which myeloid progenitor cells are transformed by a single chromosomal translocation where the Bcr domain of chromosome 22 is placed adjacent to the proto-oncogene c-Abl of chromosome 9, resulting in constitutive Abl tyrosine kinase activity. This has a twofo...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-014-2556-z
更新日期:2014-10-01 00:00:00
abstract::Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we ...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 临床试验,杂志文章
doi:10.1007/BF00686551
更新日期:1995-01-01 00:00:00
abstract:PURPOSE:The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances cisplatin [cis-diammine dichloroplatinum (II)] (CDDP)-induced apoptosis in the oral squamous cell carcinoma (OSCC) cell line by complex, multifunctional mechanisms. We investigated the role of endoplasmic reticulum (ER) stress i...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-009-0969-x
更新日期:2009-11-01 00:00:00
abstract:OBJECTIVES:We evaluated whether DNA repair gene polymorphisms had an effect on clinical outcomes in metastatic/recurrent nasopharyngeal carcinoma (NPC) patients treated with cisplatin-based chemotherapy. MATERIALS AND METHODS:Clinical data of 101 patients with metastatic/recurrent NPC between 2004 and 2011 were review...
journal_title:Cancer chemotherapy and pharmacology
pub_type: 杂志文章
doi:10.1007/s00280-013-2196-8
更新日期:2013-08-01 00:00:00