WO2006004360A1 - Procede pour renforcer l'effet d'un anticancereux par inhibition de l'activite ampk - Google Patents

Procede pour renforcer l'effet d'un anticancereux par inhibition de l'activite ampk Download PDF

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Publication number
WO2006004360A1
WO2006004360A1 PCT/KR2005/002103 KR2005002103W WO2006004360A1 WO 2006004360 A1 WO2006004360 A1 WO 2006004360A1 KR 2005002103 W KR2005002103 W KR 2005002103W WO 2006004360 A1 WO2006004360 A1 WO 2006004360A1
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WIPO (PCT)
Prior art keywords
cancer
ampk
drug
cells
activity
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PCT/KR2005/002103
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English (en)
Inventor
Joohun Ha
Myunggyu Park
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Md Bioalpha Co., Ltd.
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Priority to EP05765959A priority Critical patent/EP1765393A1/fr
Publication of WO2006004360A1 publication Critical patent/WO2006004360A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a method for enhancing anti-cancer effects of an anti-cancer drug by inhibition of AMP-activated protein kinase ("AMPK”) activity in conjunction with use of a drug for inhibiting growth and/or metastasis of cancer("anti-cancer drug").
  • AMPK AMP-activated protein kinase
  • AMPK is a serine/threonine protein kinase that is activated within the cell in response to diverse stress conditions causing depletion of cellular energy, thereby playing a central role in the maintenance of cell energy homeostasis, and is an essential protein for cellular existence. More specifically, AMPK is known as a central protein that controls its activity by the intracellular AMP: ATP ratio in response to stress, thereby inhibiting activity of enzymes involved in ATP consumption, conversely activating enzymes implicated in ATP synthesis. That is, AMPK is activated by metabolic stresses to promote glucose uptake and fatty acid oxidation, thereby raising intracellular energy levels leading to enhanced viability of cells.
  • AMPK is a heterotrimer consisting of three subunits, i.e., an alpha catalytic subunit having catalytic activity, and non-catalytic beta and gamma subunits. Recently, cDNA sequences of these subunits were determined and isomers thereof were also discovered.
  • AMPK binds to AMP and then is phosphorylated by AMPK kinase, an upstream kinase, and the phosphorylation site is known to be Thrl72 of the catalytic alpha-subunit.
  • AMPK plays a crucial role in metabolism of cancer cells and have hypothesized that AMPK will be a critical target protein in cancer therapy.
  • anti-cancer chemotherapeutics can be broadly divided into 1) alkylating agents such as cyclophosphamide, cisplatin and nitrosourea, 2) antimetabolite agents such as fluorouracil and methotrexate, 3) anti ⁇ cancer antibiotics such as actinomycin-D, doxorubicin, adriamycin, mitomycin C and bleomycin, and 4) alkaloids such as vinblastine, vincristine, vindesine and etoposide.
  • alkylating agents such as cyclophosphamide, cisplatin and nitrosourea
  • antimetabolite agents such as fluorouracil and methotrexate
  • anti ⁇ cancer antibiotics such as actinomycin-D, doxorubicin, adriamycin, mitomycin C and bleomycin
  • alkaloids such as vinblastine, vincristine, vindesine and etoposide.
  • Cisplatin cis- diamminedichloroplatinum; CDDP
  • CDDP the alkylating agent
  • Cisplatin is one of the most useful drugs among about 30 anti-cancer drugs that are in clinical use at present, and is therapeutically effective on various cancers such as testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, gastric cancer, cervical cancer and prostate cancer.
  • Cisplatin is capable of forming a cisplatin-DNA adduct and thus cisplatin intrastrand or interstrand cross- link adduct inhibits DNA replication and transcription.
  • Cisplatin hinders growth of cancer cells and induces cellular apoptosis.
  • Cisplatin-induced apoptosis is accomplished by expression of the intracellular signaling proteins due to DNA damage and signaling pathways of these proteins play a crucial role in death of cancer cells.
  • DNA damage reference is made to p53 that is a tumor suppressor protein. Entrance of DNA damage-producing stimulants into cells results in increased expression of p53 which in turn regulates a representative downstream protein, p21, responsible for halting the cellular life cycle and inducing repair of damaged DNA. In this connection, excessive stimulus may also induce expression of Bax protein, which is a downstream pro-apoptotic protein, thereby leading to cell death.
  • the activity of p53 is regulated by numerous mechanisms and an ATM/ATR kinase acts upstream of p53 pathway. In normal cells, p53 ordinarily exists bound to MDM2 protein, which is a proteasome protein and induces degradation of continuously expressed p53 via MDM2-mediated ubiquitinylation.
  • p53 When DNA damage is induced by external factors, p53 is phosphorylated to cause breakdown of binding between p53 and MDM2, and thus p53 becomes stable and increases in expression thereof. Then, p53 enters the nucleus and binds to DNA, thereby increasing transcription of target genes. Consequently, numerous methods of treating cancers via regulation of p53 signaling pathway are also reported as an important cancer therapy.
  • AMPK which is a key protein in energy metabolism induced by intracellular stress
  • AMPK will be a novel target substance crucial for anti-cancer treatment, and thus have made an attempt to confirm the role of AMPK in cancer cell-killing processes of various anti-cancer drugs that are now clinically used in anti-cancer therapy and propose possibility of combination anti ⁇ cancer therapy via regulation of AMPK.
  • anti-cancer drug a drug for inhibiting proliferation and/or metastasis of cancer
  • Cancers to which the method of the present invention can be applied include, but are not particularly limited to, testicular cancer, ovarian cancer, lung cancer, head and neck cancer, bladder cancer, gastric cancer, cervical cancer, small cell lung cancer, acute leukemia, malignant melanoma, breast cancer, hepatoma, lymphoma, multiple myeloma, colorectal cancer, pancreatic cancer, sarcoma, thyroid cancer, prostate cancer, various hematological malignancies and skin cancer.
  • cancer cells such as GAS cells causing gastric cancer, HeLa cells causing cervical cancer, Hep3B cells causing hepatoma, MCF-7 cells causing breast cancer, and DU 145 cells causing prostate cancer.
  • Anti-cancer drugs which can be utilized in the method of the present invention are also not particularly limited so long as they are drugs inhibiting proliferation and/or metastasis of cancers.
  • the alkylating agent cisplatin, the anti-cancer antibiotic doxorubicin, or the alkaloid etoposide in conjunction with inhibition of AMPK activity, exhibited enhanced anti-cancer effects of anti-cancer drugs.
  • use of cisplatin was found to be particularly preferred.
  • the method of the present invention is particularly useful for use of anti-cancer drugs that are difficult to exert anti-cancer effects thereof due to appearance of drug-resistant cancer cells.
  • AMPK inhibitors a method of administering the drugs exhibiting inhibition of AMPK activity
  • AMPK inhibitors include substances already known in the art and substances that will be newly discovered or synthesized in the future.
  • AMPK inhibitors which are known in the art for use in other application, find novel use for enhancing therapeutic effects of anti-cancer drugs by the method of the present invention.
  • AMPK inhibitors may be used before or after administration of anti ⁇ cancer drugs, or may be concurrently used with administration of anti-cancer drugs. Preferably, AMPK inhibitors are used prior to administration of anti-cancer drugs.
  • a pharmaceutical composition for preventing and treating cancer comprising a therapeutically effective amount of an AMPK inhibitor and anti-cancer drug, and a pharmaceutically acceptable carrier, diluent or excipient, or any combination thereof.
  • a method for inhibiting proliferation and/or metastasis of cancer by inhibiting activity of AMPK is provided.
  • AMPK is an essential protein for cell survival since it plays a pivotal role in the maintenance of cellular energy homeostasis through activation under diverse stress conditions causing depletion of cellular energy.
  • inhibition of AMPK activity may be fatal to cancer cells having very rapid growth rate, as compared to normal cells.
  • the anti-cancer drug may be administered in conjunction with inhibition of AMPK activity.
  • a method for preventing and treating cancer by inhibiting activity of AMPK More preferably, prophylaxis and treatment of the cancer may be accomplished by combined administration of anti-cancer drugs. Further, in accordance with the method of the present invention, it is possible to effectively eliminate cancer cells recurring after a surgical operation.
  • FIG. 1 shows results of Western blot analysis on a degree of phosphorylation of AMPK Thrl72 (“p-AMPK”) and amounts of AMPK protein (“AMPK”), and a degree of phosphorylation of ACC Ser79 (“p-ACC”) and amounts of ACC protein (“ACC”), after treatment of AGS gastric cancer cells with cisplatin in Example 1;
  • FIGS. 2 through 5 show cell viability as determined with respect to time points of cisplatin treatment and concentration thereof, upon treatment of AGS cancer cells with cisplatin after infection with AMPK-WT and AMPK-DN adenoviruses, respectively, and a degree of cellular apoptosis as determined via PI and Hoechst dye staining, in Example 2;
  • FIGS. 6 and 7 show results of Western blot analysis on a degree of phosphorylation of p53 Serl5 residue and amounts of p53 protein, upon treatment of AGS cancer cells with cisplatin after infection with AMPK-WT and AMPK-DN adenoviruses, respectively, and results of RT-PCR on a degree of synthesis of p53 and downstream target substrates, in Example 3;
  • FIG. 8 shows cell viability as determined, upon treatment of cancer cells with cisplatin after infection of HCT116p53-/- cancer cells, HCT116p53+/+ cancer cells and wild type p53-transfected HCTl 16 p53-/- cancer cells with AMPK-WT and AMPK-DN adenoviruses, respectively, in Example 3;
  • FIG. 9 shows results of Western blot analysis on a degree of phosphorylation ofp53 Serl5 residue ("p-p53”), amounts of p53 protein ("p53”) and amounts of p21 protein (“p21”), 6 hours after treatment of 30 ⁇ M cisplatin or combination treatment of
  • FIGS. 10 and 11 show micrographs of cellular morphology upon treatment of various kinds of cancer cells with various anti-cancer drugs following infection with AMPK-WT and AMPK-DN adenoviruses, respectively, in Example 3.
  • AGS, HCTl 16, DU145, MCF-7, Hep3B, and HeLa cells were, respectively, added to RPMIl 640 media supplemented with 10% fetal bovine serum and incubated at
  • Cisplatin 37 ° C with supply of 5% CO 2 .
  • Cisplatin was purchased from Sigma, and Anti-phospho
  • Acetyl-CoA carboxylase, and phospho p53 (Serl5) and p53 antibodies were purchased from Cell Signaling Technology. 2. Western Blot Analysis
  • Cancer cells were lysed in a lysis buffer containing 1% NP-40 with addition of a phosphatase inhibitor and 30 g of proteins obtained from the cell lysates were subjected to 10% SDS-polyacrylamide gel electrophoresis.
  • Activity of AMPK was determined by measuring phosphorylation of acetyl-CoA carboxylase (Ser79) that is an intracellular substrate for AMPK. Phosphorylation or expression of p53 was determined utilizing phospho-p53 (Serl5) antibodies or p53 antibodies. Expression of the thus- infected AMPK construct was determined using C-myc 9E10 antibodies.
  • Cell viability was assessed by the trypan blue dye exclusion test. In addition, cell viability was also measured using 3-(4,5-dimethylthiazolyl)-2,5- diphenyltetrazolium bromide (MTT) assay. Cellular apoptosis was determined using
  • FACS and confocal microscopy after direct infusion of propidium iodide (PI) dyes and Hoechst dyes into cells.
  • PI propidium iodide
  • AMPK subunit cDNA has an Asp 157 to Ala substitution therein and is incapable of serving as a kinase.
  • This cDNA was cloned into an adenovirus shuttle vector, pAVl, which was then co-transformed into a human embryonic kidney 293 cell in conjunction with El -deleted adenovirus serotype genome, thereby purifying recombinant adenoviruses. Purified adenoviruses were mixed into a serum-free growth medium and allowed to stand in cells for 2 hours. Then, a complete medium was added thereto and experiments were carried out after 24 hours.
  • RNAs were isolated using TRIzol (Life Technologies, Glasgow, United Kingdom), and cDNAs were synthesized using a cDNA synthesis Kit (Amersham Pharmacia Biotech, Piscataway, New Jersey). Next, PCR amplification was carried out using specific primers for respective substrates:
  • Bax sense 5'-GCGAATTCCATGGACGGGTCCGGGGAG-S'
  • ⁇ -actin sense 5 1 -GTGGGGGCGCCCAGGCACCA-3 l ,
  • Example 1 This example was designed to confirm whether the DNA damaging agent cisplatin activates AMPK. Specifically, AGS gastric cancer cells were treated with 0, 7.5, 15, 30, 60 and 90 ⁇ M cisplatin, respectively. 1 hour later, phosphorylation of AMPK Thrl72 ("p-AMPK”) and amounts of AMPK protein (“AMPK”), and phosphorylation of ACC Ser79 (“p-ACC”) and amounts of ACC protein (“ACC”) were respectively measured by Western blot analysis.
  • p-AMPK phosphorylation of AMPK Thrl72
  • AMPK AMPK protein
  • ACC Ser79 phosphorylation of ACC Ser79
  • ACC ACC protein
  • AGS gastric cancer cells were infected with recombinant adenoviruses capable of expressing the dominant negative cDNA of AMPK, and effects of the anti-cancer drug cisplatin on cell viability were measured by MTT assay and were compared with a control group.
  • FIGS. 2 through 5 apoptotic effects of cisplatin were very insignificant in AGS gastric cancer cells and thus cisplatin exhibited substantially no effect on cell viability.
  • activity of AMPK was inhibited
  • cisplatin exhibited very distinctive anti-cancer effects and thus it was observed that about 60% of cancer cells were killed within 24 hours.
  • a substantial mechanism of such cell-killing is apoptosis. More specifically, where cisplatin was treated to cells from which activity of AMPK was inhibited, Hoechst dye staining revealed that cellular nuclei were condensed.
  • PI dye staining showed increased cell populations at the subGO stage of the cell cycle, and these results demonstrate that cells were dying from apoptosis. Therefore, it is expected that combination therapy via inhibition of AMPK activity will also exert improved anti-cancer effects on cisplatin-resistant cancer cells.
  • Cisplatin is known to serve as a DNA damaging agent and to thereby increase expression and activity of the p53 protein having tumor-suppressing activity, resulting in blockage of cancer cell proliferation or cell death. It is known that activation of the p53 protein is modulated by various post-translational modifications and a phosphorylation process is also a very important regulatory mechanism in activation of the p53 protein. p53 contains numerous phosphorylation sites. Among these sites, phosphorylation of Serl5 plays the most important role and leads to increased activity of p53 protein and stabilization thereof in cytoplasm thereby resulting in increased amount of expressed p53 protein. Therefore, this experiment was designed to confirm the correlation between inhibition of AMPK activity and p53.
  • AGS cells were infected with AMPK-WT and AMPK-DN, respectively. After 24 hours of infection, cells were treated with 30 ⁇ M of cisplatin for 12 hours, and phosphorylation of the p53 Serl5 residue ("p- p53") and amounts of p53 protein ("p53”) were measured by Western blot analysis.
  • AMPK expressed in infected cells contains the c-myc epitope and therefore, expression amounts thereof were determined using c-myc antibodies.
  • RT-PCR was performed to quanitfy expression of p53 and p21, and Bax.
  • cell viability was determined using HCT116p53+/+ cells, HCTl 16p53-/- cells and wild-type p53-transfected HCTl 16 ⁇ 53-/- cells.
  • HCT116p53-/- cells According to experiments utilizing HCT116p53+/+ cells, HCT116p53-/- cells and wild-type p53-transfected HCT116p53-/- cells, such events induced by cisplatin in conjunction with inhibition of AMPK were suppressed in HCT116p53-/- cells.
  • Cisplatin as a DNA damaging agent, is known to phosphorylate the Ser-15 residue of p53 via the ATR pathway. Therefore, this experiment was carried out to confirm whether phosphorylation at the Ser-15 residue of p53 by inhibition of AMPK is correlated with the ATR pathway.
  • AGS cells were infected with AMPK- WT and AMPK-DN 5 respectively. After 24 hours of infection, cells were treated with 30 ⁇ M cisplatin or were co-treated with 30 ⁇ M cisplatin plus the ATR inhibitor caffeine.
  • AMPK expressed in infected cells contains the c- myc epitope and therefore, expression amounts thereof were determined using c-myc antibodies.
  • doxorubicin, etoposide and cisplatin are representative. This experiment was carried out to observe cell-killing effects exhibited by inhibition of AMPK in various cancer cells utilizing these anti-cancer drugs. Specifically, HeLa (human cervical cancer cell line), Hep3B (human hepatocellular carcinoma cell line), MCF-7 (human breast cancer cell line) and DU 145 (human prostate cancer cell line) were infected with AMPK-WT and AMPK-DN adenoviruses, respectively.
  • the method in accordance with the present invention can significantly enhance therapeutic effects of an anti-cancer drug via inhibition of AMPK activity and therefore is very useful in inhibition of cancer proliferation and activity, utilizing anti-cancer drugs.
  • the present invention enables use of conventional anti-cancer drugs for cancer cells having drug-resistance to such anti-cancer drugs and is expected to provide effects that can effectively eliminate cancer cells recurring after surgical operations.

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Abstract

La présente invention concerne un procédé permettant de renforcer les effets thérapeutiques d'un anticancéreux par inhibition de l'activité AMPK en association avec l'utilisation d'un anticancéreux destiné à inhiber la prolifération et/ou la métastase cancéreuse. Le procédé de l'invention, qui permet de renforcer de façon significative les effets thérapeutiques d'un anticancéreux par inhibition de l'activité AMPK, convient par conséquent particulièrement à 'inhibition de la prolifération et de la métastase cancéreuses, lorsqu'on utilise des anticancéreux. L'invention permet en outre l'utilisation anticancéreux conventionnel pour des cellules cancéreuses présentant une résistance à de tels médicaments.
PCT/KR2005/002103 2004-07-02 2005-07-02 Procede pour renforcer l'effet d'un anticancereux par inhibition de l'activite ampk WO2006004360A1 (fr)

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EP05765959A EP1765393A1 (fr) 2004-07-02 2005-07-02 Procede pour renforcer l'effet d'un anticancereux par inhibition de l'activite ampk

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010056677A1 (fr) * 2008-11-12 2010-05-20 Duke University Procédés d’inhibition du développement de cellules cancéreuses par des inhibiteurs de hdac et procédés de criblage des inhibiteurs de hdac10
WO2014180908A1 (fr) * 2013-05-08 2014-11-13 Deutsches Krebsforschungszentrum Inhibition de la cachexie du cancer au moyen d'acides/peptides

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EVANS M.J. ET AL: "Fibroblast growth factor-2 in remodeling of the developing basement membrane zone in the trachea of infant rhesus monkeys sensitized and challenged with allergen", LAB. INVEST., vol. 82, no. 12, December 2002 (2002-12-01), pages 1747 - 1754 *
KATO A. ET AL: "Critical roles of AMP-activated protein kinase in constitutive tolerance of cancer cells to nutrient deprivation and tumor formation", ONCOGENE, vol. 21, no. 39, September 2002 (2002-09-01), pages 6082 - 6090 *
SUZUKI A. ET AL: "ARK5 suppresses the cell death induced by nutrient starvation and death receptors via inhibition of caspase 8 activation, but not by chemotherapeutic agents or UV irradiation", ONCOGENE, vol. 22, no. 40, September 2003 (2003-09-01), pages 6177 - 6182 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010056677A1 (fr) * 2008-11-12 2010-05-20 Duke University Procédés d’inhibition du développement de cellules cancéreuses par des inhibiteurs de hdac et procédés de criblage des inhibiteurs de hdac10
US8664182B2 (en) 2008-11-12 2014-03-04 Duke University Methods of inhibiting cancer cell growth with HDAC inhibitors and methods of screening for HDAC10 inhibitors
WO2014180908A1 (fr) * 2013-05-08 2014-11-13 Deutsches Krebsforschungszentrum Inhibition de la cachexie du cancer au moyen d'acides/peptides

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EP1765393A1 (fr) 2007-03-28
KR20060066610A (ko) 2006-06-16

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