A new synthetic HDAC inhibitor, MHY218, induces apoptosis or autophagy-related cell death in tamoxifen-resistant MCF-7 breast cancer cells.

Abstract:

:Acquired resistance to tamoxifen (Tam) is a critical problem in breast cancer therapy. Therefore, new potential strategies for Tam-resistant breast cancer are needed recently. In this study, we synthesized a novel histone deacetylase (HDAC) inhibitor, MHY218, for the development of potent inhibitors of HDAC and evaluated its biological activities by monitoring the anticancer effects in Tam-resistant MCF-7 (TAMR/MCF-7) cells via in vitro and in vivo studies. MHY218 significantly inhibited the proliferation of TAMR/MCF-7 cells in a dose-dependent manner. The total HDAC enzyme activity was significantly inhibited, corresponding with inhibition of acetylated H3 and H4 expression in TAMR/MCF-7 cells. HDAC1, 4, and 6 expression levels were decreased in response to MHY218 treatment. Cell cycle analysis indicated that MHY218 induced G2/M phase cell cycle arrest. As expected, apoptotic cell death was observed in response to MHY218 treatment. Interestingly, levels of beclin-1 and LC3-II, the markers of autophagy, were increased in TAMR/MCF-7 cells treated with MHY218. The efficacy of MHY218 was also compared with that of SAHA in vivo in a xenograft model of nude mice bearing a TAMR/MCF-7 cells. MHY218 (10 mg/kg, twice a week for 21 days) completely inhibited tumor growth and MHY218 markedly inhibited the expression of proliferative cell nuclear antigen (PCNA) in tumor tissue. These results indicate that MHY218 can induce caspase-independent autophagic cell death rather than apoptotic cell death. The MHY218-induced autophagic cell death could be a new strategy in the treatment of Tam-resistant human breast cancer.

journal_name

Invest New Drugs

authors

Park JH,Ahn MY,Kim TH,Yoon S,Kang KW,Lee J,Moon HR,Jung JH,Chung HY,Kim HS

doi

10.1007/s10637-011-9752-z

subject

Has Abstract

pub_date

2012-10-01 00:00:00

pages

1887-98

issue

5

eissn

0167-6997

issn

1573-0646

journal_volume

30

pub_type

杂志文章
  • Phase I study of Tomudex and Doxorubicin in patients with locally advanced, inoperable or metastatic cancer (IND.98).

    abstract:BACKGROUND:The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and Doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. PATIENTS AND METHODS:Star...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1023/B:DRUG.0000047105.38511.2a

    authors: Bjarnason GA,Charpentier D,Wong R,Goel R,Douglas L,Walsh W,Matthews S,Dent S,Seymour L,Winquist E

    更新日期:2005-01-01 00:00:00

  • Drug sensitivity of ten human tumor cell lines compared to mouse leukemia (L1210) cells.

    abstract::L1210 leukemia cells, because of their rapid growth rate in suspension culture and high growth fraction, are ideally suited to screen in vitro for cytotoxic compounds. Although L1210 cells may mimic rapidly growing tumors, they have not been effective in selecting agents active against slow growing solid tumors. We ex...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00175291

    authors: Badiner GJ,Hamilton RD,Li LH,Bhuyan BK

    更新日期:1987-01-01 00:00:00

  • A novel N-myristylated synthetic octapeptide inhibits protein kinase C activity and partially reverses murine fibrosarcoma cell resistance to adriamycin.

    abstract::This report shows that N-acylation of the protein kinase C (PKC) substrate Arg-Lys-Arg-Thr-Leu-Arg-Arg-Leu (RKRTLRRL) provides it with a potent inhibitory activity against PKC. N-myristoyl-RKRTLRRL inhibited Ca2(+)- and phosphatidylserine (PS)-dependent histone phosphorylation catalyzed by PKC with a 50% inhibitory co...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00175084

    authors: O'Brian CA,Ward NE,Liskamp RM,de Bont DB,Earnest LE,van Boom JH,Fan D

    更新日期:1991-05-01 00:00:00

  • Phase II study of vinorelbine monotherapy in anthracycline and taxane pre-treated metastatic breast cancer.

    abstract::We performed a single-institution phase II study to evaluate the efficacy and toxicities of vinorelbine monotherapy in patients previously treated with anthracyclines and taxanes. Vinorelbine was administered at a dose level of 25 mg/m² intravenously on days 1, 8, 15 and 22, every four weeks, and responses were assess...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-009-9357-y

    authors: Seo HY,Lee HJ,Woo OH,Park KH,Woo SU,Yang DS,Kim AR,Lee JB,Lee ES,Kim YH,Kim JS,Seo JH

    更新日期:2011-04-01 00:00:00

  • A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.

    abstract:BACKGROUND:Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evalu...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究

    doi:10.1007/s10637-015-0239-1

    authors: Nakayama N,Sato A,Tanaka S,Shimada K,Konishi K,Sasaki E,Hibi K,Ichikawa H,Kikuchi Y,Sakuyama T,Sekikawa T,Hayashi K,Nishina H,Tokyo Cooperative Oncology Group, Tokyo, Japan.

    更新日期:2015-08-01 00:00:00

  • Using the neurotransmitter serotonin to target imaging agents to glioblastoma cells.

    abstract::The neurotransmitter serotonin is involved in numerous bodily functions via seven different serotonin receptor subfamilies. Serotonin plays a role in gastrointestinal functions like intestinal secretion or peristalsis and neuropsychiatric events like depression or migraine. One of these subtypes has been found on glio...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9781-7

    authors: Sturzu A,Sheikh S,Klose U,Echner H,Kalbacher H,Deeg M,Nägele T,Horger M,Ernemann U,Heckl S

    更新日期:2012-12-01 00:00:00

  • Assessment of the cytotoxic effects of aporphine prototypes on head and neck cancer cells.

    abstract::Purpose Among alkaloids, abundant secondary metabolites in plants, aporphines constitute a class of compounds with interesting biological activities, including anticancer effects. The present study evaluated the anticancer activities of 14 substances, including four aporphine derivatives acquired through the biomonito...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-019-00784-6

    authors: Rodrigues-Junior DM,de Almeida Pontes NM,de Albuquerque GE,Carlin V,Perecim GP,Raminelli C,Vettore AL

    更新日期:2020-02-01 00:00:00

  • A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials.

    abstract:PURPOSE:To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. METHODS:This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and Apr...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9662-0

    authors: Le Cesne A,Yovine A,Blay JY,Delaloge S,Maki RG,Misset JL,Frontelo P,Nieto A,Jiao JJ,Demetri GD

    更新日期:2012-06-01 00:00:00

  • Discovery of LY2457546: a multi-targeted anti-angiogenic kinase inhibitor with a novel spectrum of activity and exquisite potency in the acute myelogenous leukemia-Flt-3-internal tandem duplication mutant human tumor xenograft model.

    abstract::LY2457546 is a potent and orally bioavailable inhibitor of multiple receptor tyrosine kinases involved in angiogenic and tumorigenic signalling. In biochemical and cellular assays, LY2457546 demonstrates potent activity against targets that include VEGFR2 (KDR), PDGFRβ, FLT-3, Tie-2 and members of the Eph family of re...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9640-6

    authors: Burkholder TP,Clayton JR,Rempala ME,Henry JR,Knobeloch JM,Mendel D,McLean JA,Hao Y,Barda DA,Considine EL,Uhlik MT,Chen Y,Ma L,Bloem LJ,Akunda JK,McCann DJ,Sanchez-Felix M,Clawson DK,Lahn MM,Starling JJ

    更新日期:2012-06-01 00:00:00

  • Down-regulation of P-cadherin with PF-03732010 inhibits cell migration and tumor growth in gastric cancer.

    abstract::P-cadherin is frequently up-regulated in solid tumors such as gastric, colon, lung, pancreatic and breast cancers. Although P-cadherin promotes cadherin-mediated cell adhesion, the gastric cancer-linked regulation of P-cadherin has not been extensively investigated. In this study, we found epigenetic regulation of P-c...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9710-9

    authors: Park J,Park E,Han SW,Im SA,Kim TY,Kim WH,Oh DY,Bang YJ

    更新日期:2012-08-01 00:00:00

  • Phase I trial of 5-fluorouracil by 24-hour infusion weekly.

    abstract::A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorourac...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF00874152

    authors: Haas NB,Hines JB,Hudes GR,Johnston N,Ozols RF,O'Dwyer PJ

    更新日期:1993-05-01 00:00:00

  • The new isothiocyanate 4-(methylthio)butylisothiocyanate selectively affects cell-cycle progression and apoptosis induction of human leukemia cells.

    abstract::We investigated proliferation and apoptosis induction in Jurkat T-leukemia cells by the new isothiocyanate 4-(methylthio)butylisothiocyanate (MTBITC). To help elucidate whether the effects of MTBITC are specific for cancer cells, we tested MTBITC on freshly isolated, non-transformed human peripheral T lymphocytes. The...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1023/B:DRUG.0000011788.19754.54

    authors: Fimognari C,Nüsse M,Iori R,Cantelli-Forti G,Hrelia P

    更新日期:2004-04-01 00:00:00

  • Recombinant gamma interferon in advanced breast cancer: a phase II trial.

    abstract::Fifteen patients with advanced carcinoma of the breast who had failed prior chemotherapy, were treated with recombinant gamma interferon at a dose of 2mg/m2 (1mg = 2.4 X 10(7) international units) intravenously for five consecutive days every other week. The median patient age was 51 and all patients had a performance...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00173511

    authors: Muss HB,Caponera M,Zekan PJ,Jackson DV Jr,Stuart JJ,Richards F,Cooper MR,Levin EA,Reich SD,Capizzi RL

    更新日期:1986-01-01 00:00:00

  • Echinomycin: the first bifunctional intercalating agent in clinical trials.

    abstract::Echinomycin is a quinoxaline antibiotic that was originally isolated from Streptomyces echinatus. Based on its antitumor activity against two i.p. implanted murine tumors, the B16 melanoma, and the P388 leukemia, it was brought into clinical trials by the National Cancer Institute. Recent studies on its cytotoxic acti...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章,评审

    doi:10.1007/BF00170766

    authors: Foster BJ,Clagett-Carr K,Shoemaker DD,Suffness M,Plowman J,Trissel LA,Grieshaber CK,Leyland-Jones B

    更新日期:1985-01-01 00:00:00

  • A truncated apoptin protein variant selectively kills cancer cells.

    abstract::Apoptin is a nonstructural protein encoded by one of the three open reading frames of the chicken anemia virus genome. It has attracted a great deal of interest due to its ability to induce apoptosis in multiple transformed and malignant mammalian cell lines without affecting primary and non-transformed cells. However...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-017-0431-6

    authors: Ruiz-Martínez S,Castro J,Vilanova M,Bruix M,Laurents DV,Ribó M,Benito A

    更新日期:2017-06-01 00:00:00

  • Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones.

    abstract::A series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a-d) and 7 (a-g) were synthesized with different substituted aromatic sulfonyl chlorides (R-SO(2)-Cl) and alkyl halides (R-X) and were characterized by (1)H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evalu...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-008-9130-7

    authors: Chandrappa S,Benaka Prasad SB,Vinaya K,Ananda Kumar CS,Thimmegowda NR,Rangappa KS

    更新日期:2008-10-01 00:00:00

  • First-in-human phase 1 study of novel dUTPase inhibitor TAS-114 in combination with S-1 in Japanese patients with advanced solid tumors.

    abstract::Background This first-in-human phase 1 study assessed the safety of TAS-114, a novel deoxyuridine triphosphatase inhibitor, combined with S-1 to determine its maximum tolerated dose (MTD) and recommended dose (RD). Methods In this dose-escalation study with a 3 + 3 design, TAS-114 and S-1 were concurrently administere...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究

    doi:10.1007/s10637-018-0697-3

    authors: Doi T,Yoh K,Shitara K,Takahashi H,Ueno M,Kobayashi S,Morimoto M,Okusaka T,Ueno H,Morizane C,Okano N,Nagashima F,Furuse J

    更新日期:2019-06-01 00:00:00

  • A phase I study of vitamin E, 5-fluorouracil and leucovorin for advanced malignancies.

    abstract::Six patients with incurable malignancies were originally treated with vitamin E, 3200 IU/day for fourteen days, followed by the same dose of vitamin E daily plus LCV (20 mg/m2 i.v. bolus daily x 5) with 5FU (425 mg/m2 i.v. bolus immediately following LCV). The same schedule of LCV and 5FU was repeated 4 weeks later, t...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1023/a:1006484031959

    authors: Blanke CD,Stipanov M,Morrow J,Rothenberg M,Chinery R,Shyr Y,Coffey R,Johnson DH,Leach SD,Beauchamp RD

    更新日期:2001-01-01 00:00:00

  • The notorious "drug lag" for oncology drugs in Japan.

    abstract::This study aimed to analyze the oncology "drug lag" (i.e., the delay in time required for the approval of oncology drugs) in Japan compared with that in the United States of America (US) or the European Union (EU) and to identify the factors associated with this lag. Using publicly available information, we collected ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9638-0

    authors: Yonemori K,Hirakawa A,Ando M,Hirata T,Yunokawa M,Shimizu C,Katsumata N,Tamura K,Fujiwara Y

    更新日期:2011-08-01 00:00:00

  • Early depth of tumor shrinkage and treatment outcomes in non-small cell lung cancer treated using Nivolumab.

    abstract::Background It would be useful to have criteria for predicting long-term treatment responses to immune checkpoint inhibitors (ICIs). Maximum depth of response correlates with treatment outcomes among patients receiving programmed death protein 1 axis inhibitors for non-small cell lung cancer (NSCLC). We investigated as...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-019-00770-y

    authors: Kawachi H,Fujimoto D,Morimoto T,Hosoya K,Sato Y,Kogo M,Nagata K,Nakagawa A,Tachikawa R,Tomii K

    更新日期:2019-12-01 00:00:00

  • Oral idarubicin in non-Hodgkin's lymphomas.

    abstract::Idarubicin (DMDR), a new analogue of daunorubicin, was administered orally once every 3 weeks at the dose of 40 to 45 mg/m2 to 20 evaluable patients with non-Hodgkin's lymphomas (NHL). Eighty-six percent of patients with favorable histology and 54% with unfavorable histology (intermediate and high grade as IWF) achiev...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00179594

    authors: Lopez M,Di Lauro L,Papaldo P

    更新日期:1986-01-01 00:00:00

  • Severe acute interstitial lung disease in a patient with anaplastic lymphoma kinase rearrangement-positive non-small cell lung cancer treated with alectinib.

    abstract::Alectinib, the second generation anaplastic lymphoma kinase (ALK) inhibitor, has significant potency in patients with ALK rearrangement positive non-small cell lung cancer (NSCLC), and its toxicity is generally well tolerable. We report a patient who developed severe acute interstitial lung disease after alectinib tre...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-015-0284-9

    authors: Yamamoto Y,Okamoto I,Otsubo K,Iwama E,Hamada N,Harada T,Takayama K,Nakanishi Y

    更新日期:2015-10-01 00:00:00

  • Phase II trial of taxol in patients with adenocarcinoma of the upper gastrointestinal tract (UGIT). The Eastern Cooperative Oncology group (ECOG) results.

    abstract::Taxol was administered as a 24-hour continuous infusion at 250 mg/m2 in this Phase II trial in patients with adenocarcinomas of the upper gastrointestinal tract (UGIT). Twenty-five patients were entered between July 1991 and June 1992, twenty-three were eligible and were evaluated for toxicity and twenty-two were asse...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF00873804

    authors: Einzig AI,Lipsitz S,Wiernik PH,Benson AB 3rd

    更新日期:1995-01-01 00:00:00

  • Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study.

    abstract::Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-020-00992-5

    authors: Altwairgi AK,Alghareeb WA,AlNajjar FH,Alhussain H,Alsaeed E,Balbaid AAO,Aldanan S,Orz Y,Alsharm AA

    更新日期:2020-08-27 00:00:00

  • Continuing pursuit for ideal systemic anticancer radiotherapeutics.

    abstract::Cancer is one of the major causes of death for non-transmissible chronic diseases worldwide. Conventional treatments including surgery, chemotherapy and external beam radiotherapy are generally far from curative. Complementary therapies are attempted for achieving more successful treatment response. Systemic targeted ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审

    doi:10.1007/s10637-011-9758-6

    authors: Cona MM,Wang H,Li J,Feng Y,Chen F,de Witte P,Verbruggen A,Ni Y

    更新日期:2012-10-01 00:00:00

  • Silibinin ameliorates oxidative stress induced aberrant crypt foci and lipid peroxidation in 1, 2 dimethylhydrazine induced rat colon cancer.

    abstract::Pharmacological intervention to reduce CRC mortality entails the use of oral agents that can avert carcinogenesis. Silibinin, a major component of silymarin isolated from Silybum marianum (L.) was found to possess attractive remedial features. An in vivo study was designed to elucidate the effect of silibinin on the f...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-009-9237-5

    authors: Sangeetha N,Aranganathan S,Nalini N

    更新日期:2010-06-01 00:00:00

  • Multicenter phase II study of amrubicin, 9-amino-anthracycline, in patients with advanced non-small-cell lung cancer (Study 1): West Japan Thoracic Oncology Group (WJTOG) trial.

    abstract:PURPOSE:Amrubicin is a novel 9-aminoanthracycline. This multicenter phase II study was conducted to evaluate the efficacy and safety of amrubicin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS:Sixty-one previously untreated patients with stage III or IV NSCLC were entered this study. The pat...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1007/s10637-006-5937-2

    authors: Sawa T,Yana T,Takada M,Sugiura T,Kudoh S,Kamei T,Isobe T,Yamamoto H,Yokota S,Katakami N,Tohda Y,Kawakami A,Nakanishi Y,Ariyoshi Y

    更新日期:2006-03-01 00:00:00

  • Cytotoxic flavonoids and isoflavonoids from Erythrina sigmoidea towards multi-factorial drug resistant cancer cells.

    abstract:INTRODUCTION:Continuous efforts from scientists of diverse fields are necessary not only to better understand the mechanism by which multidrug resistant (MDR) cancer cells occur, but also to boost the discovery of new cytotoxic compounds. This work was designed to assess the cytotoxicity and the mechanism of action of ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-014-0137-y

    authors: Kuete V,Sandjo LP,Djeussi DE,Zeino M,Kwamou GM,Ngadjui B,Efferth T

    更新日期:2014-12-01 00:00:00

  • Sunitinib inducing tumor lysis syndrome in a patient treated for renal carcinoma.

    abstract::Sunitinib is an oral antityrosine kinase inhibitor that has antiangiogenic and antitumor activities. It has been approved for the treatment of advanced RCC and for imatinib-refractory gastrointestinal stromal tumors (GIST). Tumor lysis syndrom can occur in solid tumors. We report a case of patient with metastatic RCC ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-009-9275-z

    authors: Michels J,Lassau N,Gross-Goupil M,Massard C,Mejean A,Escudier B

    更新日期:2010-10-01 00:00:00

  • Phase II trial of menogaril in metastatic adenocarcinoma of the prostate. A Southwest Oncology Group study.

    abstract::Menogaril, a semisynthetic anthracycline antibiotic, was administered to patients with metastatic adenocarcinoma of the prostate. Forty-five patients with measurable disease and 45 patients with evaluable disease received 150-200 mg/m2 over 1 hour every 28 days. There were three partial responses (PR) among 87 patient...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1007/BF00873240

    authors: Taylor SA,Blumenstein BA,Stephens RL,Crawford ED,Pistone B,Hill JB

    更新日期:1994-01-01 00:00:00