WO2004078780A1 - Pharmaceutical composition containing l-seryl-l-leucine - Google Patents
Pharmaceutical composition containing l-seryl-l-leucine Download PDFInfo
- Publication number
- WO2004078780A1 WO2004078780A1 PCT/CN2004/000166 CN2004000166W WO2004078780A1 WO 2004078780 A1 WO2004078780 A1 WO 2004078780A1 CN 2004000166 W CN2004000166 W CN 2004000166W WO 2004078780 A1 WO2004078780 A1 WO 2004078780A1
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- WO
- WIPO (PCT)
- Prior art keywords
- seryl
- leucine
- cells
- cell
- dipeptide
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
- C07K5/06069—Ser-amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
Definitions
- Human leukemia HL60 cells were provided by Leukemia Research Department, China Medical Science Institute.
- L-Seryl-L-Leucine was found to be able to inhibit the growth of human liver cancer cell BEL7402 in vitro, with statistical significance (p ⁇ 0.01).
Abstract
A pharmaceutical composition comprising the dipeptide L-Seryl-L-Leucine and its use as a pharmaceutical compound for the modulation of the immune system and for the treatment of cancer.
Description
PHARMACEUTICAL COMPOSITION CONTAINING
L-SERYL-L-LEUCINE
FIELD OF IN EN ION
The present invention is related to the field of immunology and malignancy treatment on human. In particular, the present invention is directed to a peptide and its pharmaceutical compositions which are capable of modulating immune responses and cancer cell development.
BACKGROUND OF INVENTION
Peptides are known in the art for treatment of diseases and as pharmaceutical compositions. For example, US Patent No.6,191,113 discloses a peptide that has inhibitory activity for the growth of smooth muscle cells and is therefore useful for preventing and treating pathological conditions associated with growth of smooth muscle cells such as arteriosclerosis, restenosis after angioplasty, luminal stenosis after grafting blood vessel and smooth muscle sarcoma. US 6,184,208 discloses another peptide that is found to modulate physiological processes such as weight gain activity of the epithelial growth zone and hair growth. Furthermore, PCT publication No. WO 03/006492 and US Patent Application No. 10/237,405 suggested that certain peptides and their pharmaceutical compositions are biologically active and capable of modulating immune responses.
SUMMARY OF INVENTION
It is therefore an object of the present invention to conduct further studies on biological active peptides. In accordance with the object of the present invention, it has been found that the dipeptide L-Seryl-L-Leucine contains biological activity.
Thus, one aspect of the present invention relates to a pharmaceutical composition comprising the dipeptide L-Seryl-L-Leucine.
Another aspect of the present invention relates to a method of making a pharmaceutical composition comprising providing the dipeptide L-seryl-L-Leucine and mixing said dipeptide with a pharmaceutical acceptable carrier.
Another aspect of the present invention relates to a method of treatment of a human comprising administering a pharmaceutically effective dose of the dipeptide L-Seryl-L-Leucine to a human.
Another aspect of the present invention relates to the use of the dipeptide L-Seryl-L-Leucine as a pharmaceutical composition. Furthermore, the dipeptide may be used to modulate the immune system, and may also be used as a treatment for cancer.
A further aspect of the present invention is directed to a nutritional composition contain L-Seryl-L-Leucine and the use of the same for the manufacture of a nutritional supplement.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows a 7500x electron micrograph of L-Seryl-L-Leucine (20μg/ml) treated BEL7402 cell, illustrating necrosis of the cultured cancer cell.
Figure 2 shows a 9900x electron micrograph of L-Seryl-L-Leucine (20μg/ml) treated HL60 cell, illustrating karyo lysis of the cultured cell.
DETAILED DESCRIPTION
Introduction
It has been found that L-Seryl-L-Leucine has biological activity particularly in relation to immunological and anti-cancer properties. The effects of L-Seryl-L-Leucine on T lymphocyte transformation of mice, representing the function
of immunological regulation, were examined in vitro. The cell lines of human liver cancer BEL7402 and human leukemia HL60 were employed to evaluate the anti-cancer property of L-Seryl-L-Leucine. The methods described below can be found in Methodology of pharmacological experiment (third Edition) by Shuyun Xu, Rulian Bian, Xiu Chen published by People's Health Publishing House in 2002. L-Seryl-L-Leucine was synthesized by conventional methods.
Materials
Experimental animals
BALB/c Mice, 18-22g weight, provided by Experimental Animal Center, China Medical Science Institute.
Major reagents
L-Seryl-L-Leucine, was custom manufactured by American Peptide Company, Inc., USA.
Fetal bovine serum, and RPMI-1640 cell culture medium, Gibco, USA MTT, and ConA, Sigma, USA
Cell lines
Human liver cancer BEL7402 cells were provided by Cancer Research Department, China Medical Science Institute.
Human leukemia HL60 cells were provided by Leukemia Research Department, China Medical Science Institute.
1.1 The effect of L-Seryl-L-Leucine on BALB/c mouse T lymphocyte transformation
Healthy BALB/C mice were sacrificed by cervical dislocation. The spleen was isolated aseptically. Lymphocyte suspension was prepared with RPMI-1640 culture medium containing 10% fetal bovine serum, and re-suspended to cell density of 5xl06/ml. L-Seryl-L-Leucine was diluted with RPMI-1640 culture medium into
concentrations of 2μg/ml, 0.4μg/ml, 0.08μg/ml, and 0.016μg/ml. ConA working solution was prepared by adjusting concentration to lmg/ml with RPMI-1640 culture medium.
The reagents were placed onto a 96 wells cell culture plate as below. (1) L-Seryl-L-Leucine group: To each well, add in lOOμl lymphocyte suspension, 20μl ConA, and lOOμl L-Seryl-L-Leucine of various concentrations. 6 parallel sets of wells for each concentration; (2) negative control group: To each well, add in lOOμl lymphocyte suspension and 120μl RPMI-1640 culture medium (containing 10% FBS). Total 12 parallel sets of wells; (3) positive control group: to each well, add in lOOμl lymphocyte suspension, lOOμl RPMI-1640 culture medium (10% FBS), and 20μl ConA. 12 parallel sets of wells.
The prepared cell culture plates were incubated for 68 hrs at 37°C, 5% CO2. The cells were then pelleted by centrifugation at 150g for 10 minutes and the supernatant aspirated away. 50μl/well of lmg/ml MTT in RPMI-1640 was added, and the cells were re-suspended by shaking for 2 minutes. Incubation was continued for 4 hours at 37°C with 5% CO2. Centrifuge again for 10 minutes at 150g, aspirate away the supernatant and blot dry the cell pellet with filter paper. Add in each well 120μl 40mM HC1 in 2-propanol and shaken for 3 minutes. Obtain OD 70nm value with reference at 630nm by using an ELISA reader.
1.2 Results
Table 1 The effects of L-Seryl-L-Leucine on T lymphocytes transformation
Group L-Seryl-L-Leucine added N X±SD (OD)
L-Seryl-L-Leucine 2μg/ml 6 0.181+0.003*
L-Seryl-L-Leucine 0.4μg/ml 6 0.178+0.008*
L-Seryl-L-Leucine 0.08μg/ml 6 0.231±0.003*
L-Seryl-L-Leucine 0.016μg/ml 6 0.214+0.006*
Negative control - 12 0.114+0.007*
Positive control -. 12 0.139+0.001
* compared to positive control group P<0.001
1.3 Conclusion
L-Seryl-L-Leucine can promote the transformation activity of BALB/c mice T lymphocytes in vitro at concentration range of 0.016μg/ml - 2μg/ml, with statistical significance.
2.1 The inhibitory effect of L-Seryl-L-Leucine on cultured human liver cancer cell BEL7402 in vitro
Human liver cancer cell BEL7402 at logarithmic growth phase were digested with 0.05% trypsin and 0.02% EDTA for 2-3 minutes. When the sl rinkage of cytoplast and enlargement of intercellular space among cells were observed under inverted microscope, the digestion solution was aspirated. RPMI-1640 culture medium (with 10% FBS) was added immediately to terminate the digestion. The attached cells were totally removed from the wall and dispersed to form a single cell suspension. The suspended cells were collected by centrifugation at 150g for 10 minutes. The cells were washed twice in cold D-Hank's solution with centrifugation at 150g for 5 minutes. The washed cells were then counted and diluted to a density of 7 X 104/ml with RPMI-1640 culture medium containing 10% fetal bovine serum.
To a 96 well cell culture plate, add in incubation mix as below. (1)
L-Seryl-L-Leucine group: lOOμl/well BEL7402 cell suspension, lOOμl/well L-Seryl-L-Leucine working solution, with final concentration in well adjusted to 20μg/ml, lOμg/ml, and 5μg/ml. 6 parallel sets of wells per concentration. (2) negative control group: lOOμl/well BEL7402 cell suspension, lOOμl/well RPMI-1640 culture medium (containing 10% FBS), 12 parallel wells.
The cells were incubated for 68 hrs at 37°C, 5% CO2; then pelleted by a centrifugation at 150g for 10 minutes. After the supernatant was removed, 50μl/well
MTT of lmg/ml in RPMI-1640 was added to resuspend the cells by shaking for 2 minutes. The incubation was continued for 4 hours at 37°C, 5% CO2. The supernatant was removed after centrifugation at 150g for 10 minutes. After blotting dry the cell
pellet with filter paper, the cells were mixed with 120μl 40mM HCl in 2-propanol and shaken for 3 minutes. OD57onm with reference at 630nm was obtained with an ELISA reader.
2.2 Results
Table 2 The inhibitory effects of L-Seryl-L-Leucine on human liver cancer cell
BEL7402
Concentration N OD value Ratio of inhibitory(%)
20μg/ml 6 0.20+0.09 26.0*
1 Oμg/ml 6 0.26 + 0.03 5.5*
5μg/ml 6 0.25 + 0.03 10.2*
Negative control 12 0.28 + 0.04
* compared with negative control group, p< 0.01
2.3 Conclusion
At concentration of 20μg/ml to 5μg/ml, L-Seryl-L-Leucine was found to be able to inhibit the growth of human liver cancer cell BEL7402 in vitro, with statistical significance (p<0.01).
3.1 The effects of L-Seryl-L-Leucine on the ultrastructure of cultured human liver cancer cell BEL7402 under electron microscope
Human liver cancer cells BEL7402 at logarithmic growth phase were digested with 0.05% trypsin and 0.02% EDTA for 2-3 minutes. When the shrinkage of cytoplast and enlargement of intercellular space among cells occurred as observed under inverted microscope, the digestion solution was aspirated. RPMI-1640 culture medium (with 10% FBS) was added immediately to terminate the digestion. The attached cells were totally removed from the wall and dispersed to form a cell suspension. The suspended cells were collected by centrifugation at 150g for 10 minutes. The cells were washed twice in cold Hank's solution with centrifugation at 150g for 5 minutes. The washed cells were then counted and diluted to a density of 6
X 104/ml with RPMI-1640 culture medium containing 10% fetal bovine serum. 9 ml cell suspension was added into each 50 ml culture flask and left overnight for cell attachment. 1 ml solution containing L-Seryl-L-Leucine in RPMI-1640 culture medium (containing 10% fetal bovine serum) was then added to each flask so that the final concentration of L-Seryl-L-Leucine in each flask reached 20μg/ml, 1 Oμg/ml, and 5μg/ml. Two parallel flasks were prepared for each concentration. Two flasks of cells were also prepared as negative control, in which 1ml RPMI-1640 culture medium (containing 10% fetal bovine serum) and 9 ml cell suspension was included. The cells were incubated for 72 hrs at 37°C, 5% CO2 and then digested with 0.05% trypsin - 0.02% EDTA for 2-3 minutes. The digestion solution was discarded when the cells were detached from the wall of the flask as observed under inverted microscope. The detached cells were collected and washed with cold Hank's solution. After centrifugation at 150g for 5 minutes, the supernatant was removed. 4 ml cold (4°C) glutaral solution (2.5% in phosphate buffer saline pH7.4) was then added along the wall carefully to fix the cells. After dehydration, permeation, embedding, slicing, staining, the cells were observed under electron microscope.
3.2 Results
When treated with L-Seryl-L-Leucine, at all concentrations, the following alterations of BEL7402 cell ultrastructure were observed. Cellular necrosis, dissolution of plasma and organelle membranes, only left with a little membrane structures; calcium deposits found in mitochondria, with interspace among crista expanded and the crista partially disappeared with only space left behind; the heterochromatin and euchromatin in nuclei dissolved and disappeared to different extends; occasionally observed atypical apoptosis; both nuclei and cytoplasm changed to high electron density, and some bursa-like expanded rough endoplasmic reticula were observed in cytoplasm; no typical apoptosis phenomena found in nuclei.
As shown in Fig. 1, L-Seryl-L-Leucine (20μg/ml) caused necrosis of cancer cells. Both nuclei and cytoplasm appear to be involved, with concomitant degradation of the nucleoli as characterized by meticulous small vacuoles. The chromatin in the
nuclei became partially dissolved and partially concentrated. The most serious lesion being found in the cell membrane.
3.3 Conclusion L-Seryl-L-Leucine at concentration between 5μg/ml to 20μg/ml, was found to be able to induce necrosis and apoptosis of cultured human liver cancer cell BEL 7402 in vitro.
4.1 The effect of L-Seryl-L-Leucine on the proliferation of cultured human leukemia cell HL60 in vitro
Human leukemia cell HL60 at logarithmic growth phase was diluted to a density of 1 X 105/ml with RPMI-1640 culture medium containing 10% fetal bovine serum. lOOμl/well HL60 cell suspension and lOOμl/well stock L-Seryl-L-Leucine solution were added into a 96 wells culture plate so as to make up final concentrations of L-Seryl-L-Leucine to 20μg/ml. 6 parallel sets of wells. For the negative control group, add in lOOμl/well HL60 cell suspension and lOOμl/well RPMI-1640 culture medium( containing 10% FBS). 12 parallel sets of wells. The cells were incubated for 68 hrs at 37°C, 5% CO2, then pelleted with centrifugation at 150g for 10 minutes. After the supernatant was removed, the cells were resuspended with 50μl/well MTT solution (lmg/ml) in RPMI-1640 by shaking for 2 minutes. Incubation was continued for 4 hours. The supernatant was removed by centrifugation at 150g for 10 minutes. After blotting dry with filter paper, the cell pellet was mixed with 120μl 40mM HCl in 2-propanol and shaken for 3 minutes. OD5 0nm of each well referenced at 630nm was obtained with ELISA reader.
4.2 Results
Table 3 The inhibitory effects of L-Seryl-L-Leucine on human leukemia cell HL60
Group N OD value Ratio of inhibitory(%)
L-Seryl-L-Leucine 6 0.22+0.04 19.6* Negative control 12 0.27±0.05
* compared with negative control, p<0.05
4.3 Conclusion
The growth of human leukemia cell HL60 in vitro was inhibited by L-Seryl-L-Leucine at concentration 20μg/ml.
5.1 The effects of L-Seryl-L-Leucine on the ultrastructure of cultured human leukemia cell HL60 under electron microscope
Human liver cancer cell BEL7402 at logarithmic growth phase was diluted with RPMI-1640 culture medium (containing 10% fetal bovine serum) to a density of
1 X 105/ml. 9 ml cell suspension was transferred into a 50 ml culture flask. 1 ml solution of L-Seryl-L-Leucine dissolved with RPMI-1640 culture medium (containing
10% fetal bovine serum) was added into the flask to reach a final concentration of
20μg/ml, 1 Oμg/ml, and 5μg/ml. Two flasks of cells were prepared for each concentration. Two flasks of cells with 1ml RPMI-1640 culture medium (containing
10% fetal bovine serum) added to 9 ml cell suspension were used as negative control.
The cells were incubated for 72 hrs at 37°C, 5% CO2 . After centrifugation at 150g for
5 minutes, the supernatant was removed. 4 ml cold (4°C) glutaral solution (2.5% in phosphate buffer saline pH7.4) was then added along the wall carefully to fix the cells. After dehydration, permeation, embedding, slicing, staining, the cells were observed under electron microscope.
5.2 Results
When treated with L-Seryl-L-Leucine, at all tested concentrations, the following alterations of HL60 cell ultrastructure were observed. Plasma membrane was disrupted with the disintegration of mitochondria and endoplasmic reticula. There also appeared plenty of lysosomes and various vacuoles and membranous structures. Lots of apoptotic cells were found which were shrunken and round-shaped. The cell surface structure had disappeared. Dark staining and abnormally lobed nuclei had appeared and increased electron density can be seen at the edge of cytoplasm. The
nuclei and cytoplasm showed nearly the same electron density. Endoplasmic reticula vacuoles and round lipid vacuoles were common in most cells. As shown in Fig. 2, L-Seryl-L-Leucine (20μg/ml) caused the human leukemia cell HL60 to undergo karyolysis.
5.3 Conclusion
L-Seryl-L-Leucine at concentration between 5μg/ml to 20μg/ml was found to be able to induce necrosis and apoptosis of cultured human leukemia cell HL60 in vitro.
Claims
1. A pharmaceutical composition comprising the dipeptide L-Seryl-L-Leucine.
2. A pharmaceutical composition according to claim 1 wherein the dipeptide is substantially pure.
3. A method of making a pharmaceutical composition comprising providing the dipeptide L-Seryl-L-Leucine and mixing said dipeptide with a pharmaceutically acceptable carrier.
4. A method of treatment of a human comprising administering a pharmaceutically effective dose of the dipeptide L-Seryl-L-Leucine to a human.
5. The use of the dipeptide L-Seryl-L-Leucine as a pharmaceutical compound.
6. The use according to claim and 5 wherein said compound is used for the treatment of cancer.
7. The use according to claim 5 wherein said compound is used for the modulation of the immune system.
8. The use according to claim 6 wherein said cancer is liver cancer or leukemia.
9. The use of the dipeptide L-Seryl-L-Leucine as a nutritional supplement.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45250903P | 2003-03-04 | 2003-03-04 | |
| US60/452,509 | 2003-03-04 |
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| Publication Number | Publication Date |
|---|---|
| WO2004078780A1 true WO2004078780A1 (en) | 2004-09-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/CN2004/000166 WO2004078780A1 (en) | 2003-03-04 | 2004-03-03 | Pharmaceutical composition containing l-seryl-l-leucine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007053390A2 (en) * | 2005-10-28 | 2007-05-10 | Nestec S.A. | Methods for the use of branched chain amino acids |
| EP1941896A1 (en) * | 2005-09-20 | 2008-07-09 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptide-containing composition for oral administration |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014114A1 (en) * | 1992-01-09 | 1993-07-22 | The Scripps Research Institute | Peptide linkage unit comprising methylene phosphinic acid |
| WO1997025351A2 (en) * | 1996-01-04 | 1997-07-17 | Leukosite, Inc. | INHIBITORS OF MAdCAM-1-MEDIATED INTERACTIONS AND METHODS OF USE THEREFOR |
| WO1998006849A1 (en) * | 1996-08-13 | 1998-02-19 | Zymogenetics, Inc. | Expression vectors, cells, and methods for preparing thrombopoietin polypeptides |
-
2004
- 2004-03-03 WO PCT/CN2004/000166 patent/WO2004078780A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014114A1 (en) * | 1992-01-09 | 1993-07-22 | The Scripps Research Institute | Peptide linkage unit comprising methylene phosphinic acid |
| WO1997025351A2 (en) * | 1996-01-04 | 1997-07-17 | Leukosite, Inc. | INHIBITORS OF MAdCAM-1-MEDIATED INTERACTIONS AND METHODS OF USE THEREFOR |
| WO1998006849A1 (en) * | 1996-08-13 | 1998-02-19 | Zymogenetics, Inc. | Expression vectors, cells, and methods for preparing thrombopoietin polypeptides |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1941896A1 (en) * | 2005-09-20 | 2008-07-09 | Kyowa Hakko Kogyo Co., Ltd. | Dipeptide-containing composition for oral administration |
| EP1941896A4 (en) * | 2005-09-20 | 2010-01-27 | Kyowa Hakko Bio Co Ltd | Dipeptide-containing composition for oral administration |
| US7846902B2 (en) | 2005-09-20 | 2010-12-07 | Kyowa Hakko Bio Co., Ltd. | Dipeptide-comprising composition for oral administration |
| WO2007053390A2 (en) * | 2005-10-28 | 2007-05-10 | Nestec S.A. | Methods for the use of branched chain amino acids |
| WO2007053390A3 (en) * | 2005-10-28 | 2007-08-09 | Novartis Ag | Methods for the use of branched chain amino acids |
| EP2340725A1 (en) * | 2005-10-28 | 2011-07-06 | Nestec S.A. | Methods for the use of branched chain amino acids |
| US7989418B2 (en) | 2005-10-28 | 2011-08-02 | Nestec S.A. | Methods for the use of branched chain amino acids |
| AU2006309040B2 (en) * | 2005-10-28 | 2011-10-06 | Nestec S.A. | Methods for the use of branched chain amino acids |
| US8486888B2 (en) | 2005-10-28 | 2013-07-16 | Nestec S.A. | Methods for use of branched amino acids |
| EP2630874A1 (en) * | 2005-10-28 | 2013-08-28 | Nestec S.A. | Methods for the use of branched chain amino acids |
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