The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells.

Abstract:

:Melanoma is the most lethal human skin cancer. If metastatic, it becomes very aggressive and resistant to standard modalities of anticancer treatment. During the last 10 years, several therapeutic strategies have been tested including the use of single and combined small drugs. Experimental results indicate that RAS and PI3K pathways are important for the development and maintenance of melanoma. In this study, we assessed the in vitro and in vivo inhibition potential of PI-103, a PI3K (p110alpha)/mTOR inhibitor and sorafenib, a BRAF inhibitor, as single agents and in combination in primary melanoma cell lines. Although PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway appeared to be more effective. The combination of the two agents in in vitro showed a synergistic effect inhibiting RAS and PI3K pathways in a cell line dependent manner. However, no cooperative effect was observed in blocking in vivo tumor growth in immunocompetent mice. In contrary to the expected, the data indicate that PI-103 induced immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. Furthermore, in vitro studies examining the effects of the PI3K/mTOR inhibitor in tumor derived cell lines indicated that PI-103 induced the anti-apoptotic BH3 family proteins Mcl1, Bcl2 and Bcl(xL) favoring, the in vitro survival of sorafenib treated melanoma cells. These data certainly makes an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models prior to conducting clinical studies.

journal_name

Int J Cancer

authors

López-Fauqued M,Gil R,Grueso J,Hernandez-Losa J,Pujol A,Moliné T,Recio JA

doi

10.1002/ijc.24926

subject

Has Abstract

pub_date

2010-04-01 00:00:00

pages

1549-61

issue

7

eissn

0020-7136

issn

1097-0215

journal_volume

126

pub_type

杂志文章
  • Expression of differentiation antigens within human mammary tumours is related to response to endocrine therapy and survival.

    abstract::Human mammary tumours which are histologically well differentiated are more likely to synthesize receptors for estrogen (ER) and progesterone (PR) and to respond to systemic endocrine therapy. The aim of this study was to explore the relationship between differentiation, receptors and endocrine responsiveness in more ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910420203

    authors: Baildam AD,Howell A,Barnes DM,Redford J,Healy K,Swindell R,Sellwood RA

    更新日期:1988-08-15 00:00:00

  • A bivalent single-chain antibody-toxin specific for ErbB-2 and the EGF receptor.

    abstract::ErbB-2 and EGF receptors are often co-expressed in human tumors and have been shown to synergize in the transformation of cells in experimental model systems. Transactivation of ErbB-2 can occur via ligand-induced heterodimerization with EGF receptor or other members of the ErbB family of receptor tyrosine kinases. We...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(SICI)1097-0215(19960208)65:4<538::AID-IJC

    authors: Schmidt M,Hynes NE,Groner B,Wels W

    更新日期:1996-02-08 00:00:00

  • Functional impact of sequence variation in the promoter region of TGFB1.

    abstract::Pathological deregulation of the transforming growth factor, beta 1 (TGFB1) pathway has been implicated in the development of several major diseases, including cancers. Regulatory variation in the TGFB1 gene may lead to altered TGFB1 expression and activity, and thus, modulate an individual's susceptibility to disease...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.24526

    authors: Healy J,Dionne J,Bélanger H,Larivière M,Beaulieu P,Labuda D,Sinnett D

    更新日期:2009-09-15 00:00:00

  • Seroepidemiologic survey of captive Old-World primates for antibodies to human and simian retroviruses, and isolation of a lentivirus from sooty mangabeys (Cercocebus atys).

    abstract::Sera from 526 Old-World monkeys and apes, representing 50 species and 20 genera and living in US zoos and vivaria, were screened for antibodies to HTLV-I, HTLV-III/LAV, and simian-AIDS retrovirus, type I (SRV-I). Sera were screened initially by ELISA, and ELISA-positive sera, as well as ELISA-negative sera from cage c...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910380417

    authors: Lowenstine LJ,Pedersen NC,Higgins J,Pallis KC,Uyeda A,Marx P,Lerche NW,Munn RJ,Gardner MB

    更新日期:1986-10-15 00:00:00

  • The role of PGP9.5 as a tumor suppressor gene in human cancer.

    abstract::PGP9.5 is a controversial molecule from an oncologic point of view. We recently identified frequent methylation of PGP9.5 gene exclusively in primary head and neck squamous cell carcinoma (HNSCC), suggesting that it could be a tumor suppressor gene. On the other hand, PGP9.5 was reported to be overexpressed in a subse...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.23354

    authors: Tokumaru Y,Yamashita K,Kim MS,Park HL,Osada M,Mori M,Sidransky D

    更新日期:2008-08-15 00:00:00

  • Membrane association and shedding of the GPI-anchored Ca-MOv18 antigen in human ovary carcinoma cells.

    abstract::The antigen recognized by the MOv18 MAb (Ca-MOv18) was recently shown to be a glycosylphosphatidylinositol (GPI)-linked protein. In this report we show that GPI-anchorage is not limited to IGROVI cells nor to other ovary carcinoma cell lines, but Ca-MOv18 was also found to be sensitive to phosphatidylinositol-specific...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910510326

    authors: Miotti S,Alberti S,Facheris P,Mantovani L,Fornaro M,Stella M,Ménard S,Canevari S,Colnaghi MI

    更新日期:1992-05-28 00:00:00

  • Cell proliferation in 3,800 node-negative breast cancers: consistency over time of biological and clinical information provided by 3H-thymidine labelling index.

    abstract::For breast cancer, many prognostic markers that initially appeared promising have failed to maintain their clinical predictive value. Few reports have analyzed the consistency over time of biological and clinical information provided by biomarkers. Tumour cell proliferation has acquired relevance as an indicator of pr...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19970220)74:1<122::aid-ijc

    authors: Silvestrini R,Daidone MG,Luisi A,Mastore M,Leutner M,Salvadori B

    更新日期:1997-02-20 00:00:00

  • Differences in the post-translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells.

    abstract::The identification of (gamma-glutamyl)polyamines in proteolytic digest of proteins from the cytosolic and particulate fractions of B16-F10 and B16-F10Lr6 cell lines, originating from a spontaneous tumor in C57BL/6 mice, indicates that polyamines are incorporated into melanoma cell proteins by transglutaminases (TGases...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910530515

    authors: Beninati S,Abbruzzese A,Cardinali M

    更新日期:1993-03-12 00:00:00

  • Childhood cancers in Chennai, India, 1990-2001: incidence and survival.

    abstract::Childhood cancers (age at diagnosis: 0-14 years) comprise a variety of malignancies, with incidence varying worldwide by age, sex, ethnicity and geography, that provide insights into cancer etiology. A total of 1,334 childhood cancers registered in population-based cancer registry, Chennai, India, during 1990-2001 and...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.23428

    authors: Swaminathan R,Rama R,Shanta V

    更新日期:2008-06-01 00:00:00

  • Calcium-sensing receptor silencing in colorectal cancer is associated with promoter hypermethylation and loss of acetylation on histone 3.

    abstract::The calcium-sensing receptor (CaSR) is suggested to mediate the antiproliferative effects of calcium in colon. However, in colorectal cancer (CRC) the expression of the CaSR is silenced and the underlying mechanisms leading to its loss are poorly understood. We investigated whether loss of the CaSR expression in color...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.28856

    authors: Fetahu IS,Höbaus J,Aggarwal A,Hummel DM,Tennakoon S,Mesteri I,Baumgartner-Parzer S,Kállay E

    更新日期:2014-11-01 00:00:00

  • DNA ploidy and clonal selection in ras + myc-induced mouse prostate cancer.

    abstract::An important goal in prostate cancer research is to define specific molecular and cellular alterations that are associated with malignant progression. The mouse prostate reconstitution model is a relevant and useful system as it allows the study of early events in cancer progression under conditions where oncogene-ini...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910600321

    authors: Greene DR,Taylor SR,Aihara M,Yoshida K,Egawa S,Park SH,Timme TL,Yang G,Scardino PT,Thompson TC

    更新日期:1995-01-27 00:00:00

  • Prospective study of alcohol consumption and breast cancer risk in Japanese women.

    abstract::Epidemiologic evidence is lacking for the association between alcohol consumption and the risk of breast cancer in Japanese women. We addressed this association in a prospective cohort study with an average follow-up of 7.6 years. At baseline (1988-1990), cohort participants completed a self-administered questionnaire...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20980

    authors: Lin Y,Kikuchi S,Tamakoshi K,Wakai K,Kondo T,Niwa Y,Yatsuya H,Nishio K,Suzuki S,Tokudome S,Yamamoto A,Toyoshima H,Tamakoshi A

    更新日期:2005-09-20 00:00:00

  • Activation of the precursor of gelatinase A/72 kDa type IV collagenase/MMP-2 in lung carcinomas correlates with the expression of membrane-type matrix metalloproteinase (MT-MMP) and with lymph node metastasis.

    abstract::We have identified a novel membrane-type matrix metalloproteinase (MT-MMP) expressed on the cell surface and inducing activation of pro-gelatinase A in vitro. In this study, we further examined the possibility that MT-MMP is the activator of pro-gelatinase A in tumors as well as in vitro. Expression of MT-MMP mRNA was...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910640513

    authors: Tokuraku M,Sato H,Murakami S,Okada Y,Watanabe Y,Seiki M

    更新日期:1995-10-20 00:00:00

  • Phosphoglycerate kinase 1-overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti-tumor immunity in vivo.

    abstract::In addition to the known function in the glycolytic pathway, phosphoglycerate kinase 1 (PGK-1) promotes reduction of plasmin disulfide bonds leading to angiostatin formation and inhibition of tumor angiogenesis. In this study, the effects of PGK-1 on anti- tumor immunity against lung cancer were evaluated using the Te...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.23888

    authors: Tang SJ,Ho MY,Cho HC,Lin YC,Sun GH,Chi KH,Wang YS,Jhou RS,Yang W,Sun KH

    更新日期:2008-12-15 00:00:00

  • Plasma microRNA-based signatures to predict 3-year postoperative recurrence risk for stage II and III gastric cancer.

    abstract::Our aim was to identify plasma microRNA (miRNA)-based signatures to predict 3-year postoperative recurrence risk for patients with stage II and III gastric cancer (GC), so as to provide insights for individualized adjuvant therapy. Plasma miRNA expression was investigated in three phases, involving 407 patients recrui...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.30895

    authors: Liu X,Zhang X,Zhang Z,Chang J,Wang Z,Wu Z,Wang C,Sun Z,Ge X,Geng R,Tang W,Dai C,Lin Y,Lin F,Sun M,Jia W,Xue W,Ji J,Hu Y,Qin G,Li J

    更新日期:2017-11-15 00:00:00

  • Microsatellite instability and pathological aspects of breast cancer.

    abstract::Genomic instability plays a key role in hereditary nonpolyposis colorectal cancer and in a significant sub-set of non-hereditary colorectal tumors. Recent evidence suggests that microsatellite instability also occurs in various sub-sets of common, non-hereditary forms of extra-colorectal carcinoma. To investigate the ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910640409

    authors: Contegiacomo A,Palmirotta R,De Marchis L,Pizzi C,Mastranzo P,Delrio P,Petrella G,Figliolini M,Bianco AR,Frati L

    更新日期:1995-08-22 00:00:00

  • Glycoprotein 90K/MAC-2BP interacts with galectin-1 and mediates galectin-1-induced cell aggregation.

    abstract::The glycoprotein 90K was originally described as a tumor-secreted antigen and subsequently found to have immunostimulatory activity as well as other possible functions. This protein interacts with an endogenous lectin, galectin-3, and may play a role in tumor metastasis through this interaction. Because 90K is heavily...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/1097-0215(200002)9999:9999<::aid-ijc1022>3

    authors: Tinari N,Kuwabara I,Huflejt ME,Shen PF,Iacobelli S,Liu FT

    更新日期:2001-01-15 00:00:00

  • Hypermethylation of RASSF1A and BLU tumor suppressor genes in non-small cell lung cancer: implications for tobacco smoking during adolescence.

    abstract::The putative tumor suppressors RASSF1A and BLU are mapped adjacent to one another on chromosome 3p21.3, a region frequently deleted in lung cancer. These genes are often inactivated by promoter hypermethylation, but the association of this inactivation with clinical features of the disease or with carcinogen exposure ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20714

    authors: Marsit CJ,Kim DH,Liu M,Hinds PW,Wiencke JK,Nelson HH,Kelsey KT

    更新日期:2005-03-20 00:00:00

  • Chromosome 5 harbors two independent deletion hotspots at 5q13 and 5q21 that characterize biologically different subsets of aggressive prostate cancer.

    abstract::Deletion of chromosome 5q is common in prostate cancer and is linked to aggressive disease. Most previous studies focused on 5q21 where CHD1 is located, but deletion of mapping studies has identified a second deletion hotspot at 5q13. To clarify the prevalence and clinical relevance of 5q13 deletions and to determine ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.33344

    authors: Möller K,Kluth M,Ahmed M,Burkhardt L,Möller-Koop C,Büscheck F,Weidemann S,Tsourlakis MC,Minner S,Heinzer H,Huland H,Graefen M,Sauter G,Schlomm T,Dum D,Simon R

    更新日期:2021-02-01 00:00:00

  • Non-steroidal anti-inflammatory drugs and prostate cancer progression.

    abstract::Experimental studies have suggested that the biosynthesis of arachidonic acid-derived eicosanoids such as prostaglandin E2 via the cyclo-oxygenase pathway may play a significant role in supporting cell proliferation in human prostate cancer cell lines. However, the aetiological significance of this for clinical prosta...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19980812)77:4<511::aid-ijc

    authors: Norrish AE,Jackson RT,McRae CU

    更新日期:1998-08-12 00:00:00

  • Mutation and expression of the p53 gene in malignant melanoma cell lines.

    abstract::Three monoclonal antibodies (MAbs) against p53 protein (PAb 24o, DO-I and PAb1801) were used to define the immunophenotype of 13 melanoma cell lines. Immunoreactions could be detected in 12 out of 13 cell lines by using the indirect immunofluorescence technique. In 7 of these the majority of cells displayed cytoplasmi...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910540427

    authors: Weiss J,Schwechheimer K,Cavenee WK,Herlyn M,Arden KC

    更新日期:1993-06-19 00:00:00

  • Association of aspirin and other non-steroidal anti-inflammatory drug use with incidence of non-Hodgkin lymphoma.

    abstract::Non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, seem to have chemopreventive properties against several types of cancer, particularly colon cancer. Persons with rheumatoid arthritis, an autoimmune disease for which NSAIDs are used commonly, have been reported to be at lower risk of colon cancer but ...

    journal_title:International journal of cancer

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1002/ijc.11311

    authors: Cerhan JR,Anderson KE,Janney CA,Vachon CM,Witzig TE,Habermann TM

    更新日期:2003-09-20 00:00:00

  • Pharmacokinetics of methotrexate and its 7-OH metabolite in cancer patients treated with different high-methotrexate dosage regimens.

    abstract::The pharmacokinetics of methotrexate (MX) and 7-OH methotrexate (MXOH) was studied in 18 cancer patients treated with 6-hr intravenous (i.v.) infusion of 100 mg/kg (A), 80 mg/kg preceded by 20 mg/kg i.v. loading dose (B), and 70 mg/kg preceded by 30 mg/kg i.v. loading dose (C). Simultaneous analysis of MX and MXOH was...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910380603

    authors: el-Yazigi A,Amer M,Al-Saleh I,Martin C

    更新日期:1986-12-15 00:00:00

  • HER3 is required for the maintenance of neuregulin-dependent and -independent attributes of malignant progression in prostate cancer cells.

    abstract::HER3 (ERBB3) is a catalytically inactive pseudokinase of the HER receptor tyrosine kinase family, frequently overexpressed in prostate and other cancers. Aberrant expression and mutations of 2 other members of the family, EGFR and HER2, are key carcinogenic events in several types of tumors, and both are well- validat...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.24651

    authors: Soler M,Mancini F,Meca-Cortés O,Sánchez-Cid L,Rubio N,López-Fernández S,Lozano JJ,Blanco J,Fernández PL,Thomson TM

    更新日期:2009-12-01 00:00:00

  • Plasma decorin predicts the presence of esophageal squamous cell carcinoma.

    abstract::Using a microarray technique, we found decorin to be underexpressed, but osteopontin (OPN) to be overexpressed, in esophageal squamous cell carcinoma (ESCC). This study aims to examine whether plasma decorin and OPN plus personal substances use (tobacco, alcohol and areca) can serve as suitable clinical markers to pre...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.25239

    authors: Wu IC,Wu DC,Huang CC,Lin HS,Chen YK,Tsai HJ,Lu CY,Chou SH,Chou YP,Li LH,Tai SY,Wu MT

    更新日期:2010-11-01 00:00:00

  • International patterns and trends in testis cancer incidence.

    abstract::Although the incidence of testis cancer has risen markedly in many Western populations over the past half-century, it is not clear whether rates in other populations also have increased. To clarify this issue, we examined testis cancer incidence rates over the 25-year time period of 1973-1997 for selected populations ...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.20931

    authors: Purdue MP,Devesa SS,Sigurdson AJ,McGlynn KA

    更新日期:2005-07-10 00:00:00

  • Activation of protein kinase C modulates cell-cell and cell-substratum adhesion of a human colorectal carcinoma cell line and restores 'normal' epithelial morphology.

    abstract::Abnormal cell adhesion is an important contributing factor in invasion and metastasis. Here, we show that morphologically 'normal' cell-cell and cell-substratum adhesion can be restored to a poorly differentiated carcinoma cell line by activation of protein kinase C (PKC). This cell line, VACO 10MS, grows as multicell...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/(sici)1097-0215(19990129)80:3<455::aid-ijc

    authors: Cowell HE,Garrod DR

    更新日期:1999-01-29 00:00:00

  • Partial characterization of viral DNA from human genital warts (Condylomata acuminata).

    abstract::By centrifuging total cellular DNA derived from human genital warts (condylomata acuminata) in CsCl-ethidium bromide gradients, supercoiled DNA was isolated. The molecular weight of this DNA was determined by agarose gel electrophoresis and amounted to 5.1 X 10(4). This DNA isolated from an individual genital wart was...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910250509

    authors: Gissmann L,zur Hausen H

    更新日期:1980-05-15 00:00:00

  • Characterization and partial purification of human milk fat globule membrane antigens by polyacrylamide gel electrophoresis and immunoblotting using monoclonal antibodies.

    abstract::Polyclonal and monoclonal antibodies were used to characterize human milk fat globule (HMFG) membrane antigens, using gel filtration, ion exchange chromatography and western blotting. Although originally generated against HMFG, monoclonal antibodies also reacted with skim milk. In western blotting, several antigen mol...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.2910350207

    authors: Ashorn P,Krohn K

    更新日期:1985-02-15 00:00:00

  • Cancer incidence among Asian American populations in the United States, 2009-2011.

    abstract::Cancer incidence disparities exist among specific Asian American populations. However, the existing reports exclude data from large metropoles like Chicago, Houston and New York. Moreover, incidence rates by subgroup have been underestimated due to the exclusion of Asians with unknown subgroup. Cancer incidence data f...

    journal_title:International journal of cancer

    pub_type: 杂志文章

    doi:10.1002/ijc.29958

    authors: Jin H,Pinheiro PS,Xu J,Amei A

    更新日期:2016-05-01 00:00:00