CN115869316A - Application of isbanus in preparation of combined anti-breast cancer medicine - Google Patents
Application of isbanus in preparation of combined anti-breast cancer medicine Download PDFInfo
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Abstract
The invention discloses an application of isbang in preparing a combined anti-breast cancer medicament. The invention also discloses a composition which can cause the re-expression of estrogen receptor and is combined with a medicament targeting the estrogen receptor to inhibit breast cancer, and the composition contains Isatis. Due to the re-expression of estrogen receptors, tumors are re-sensitized to less toxic endocrine therapeutic drugs targeting estrogen receptors. Thus, the aim of inhibiting the growth of breast cancer, particularly triple negative breast cancer, can be achieved by using endocrine treatment medicines with lower toxicity in a combined way.
Description
Technical Field
The invention relates to application of isbans in preparation of a combined anti-tumor medicament, in particular to application of isbans in preparation of a combined anti-breast cancer medicament and a composition for combined anti-breast cancer.
Background
Breast cancer is the most common cancer in women, responsible for a large number of morbidity and mortality, of which Triple Negative Breast Cancer (TNBC) is one of the more difficult treatments because it lacks the expression of estrogen receptor (ERa) and Progesterone Receptor (PR) and does not overexpress the membrane receptor human epidermal growth factor receptor-2 (HER 2). Triple negative breast cancer patients are not candidates for targeted therapy against ERa or HER2, and treatment is limited to cytotoxic chemotherapy and radiation therapy.
Although endocrine therapy drugs are relatively less toxic, endocrine therapy targets are lacking in triple negative breast cancer, and chemotherapy drugs related to cytotoxicity are used in the first line. The preoperative neoadjuvant chemotherapy uses anthracycline cyclophosphamide and taxus chemotherapy drugs or taxus and platinum combination chemotherapy, and postoperative triple-negative breast cancer patients adopt anthracycline cyclophosphamide and taxus chemotherapy schemes. Different combinations of conventional chemotherapeutic agents are used to achieve optimal chemotherapeutic effect.
Chemotherapy drugs used conventionally can cause strong side effects, anthracyclines can cause alopecia, myelosuppression, cardiotoxicity and other toxic and side effects, and cyclophosphamide can cause gastrointestinal, hepatotoxicity, myelosuppression and nephrotoxicity. Triple negative breast cancer has poor efficacy with conventional chemotherapy, often poor prognosis, an increased risk of recurrence for 1-3 years, higher mortality in the first 5 years relative to other typed breast cancers, and a poor outcome of rapid progression from distant recurrence to death. Triple negative breast cancer employs a conventional chemotherapy regimen, rather than endocrine therapy, in that it has no relevant hormone therapy-related targets.
In triple negative breast cancer treatment, conventional chemotherapy has the disadvantages of strong toxic side effects and poor therapeutic effect, and therefore, a technical scheme capable of adopting endocrine therapy is needed.
Disclosure of Invention
The invention aims to provide a method for inhibiting growth of breast cancer, particularly triple negative breast cancer by means of targeted inhibition of kinesin superfamily member 11, so that an estrogen receptor can be expressed again in triple negative breast cancer, tumors are re-sensitive to endocrine therapy medicines which target the estrogen receptor and have low toxicity, and the endocrine therapy medicines which target the estrogen receptor are used in combination.
In one aspect, to achieve the above objects, the present invention provides the use of islastid for the preparation of a combination anti-breast cancer medicament.
Ispinesib (Isilensib, also known as SB-715992, CK-0238273) is the first small molecule inhibitor of KSP and is a potent, specific, allosteric inhibitor.
Ispinesib alters the binding of KSP to tubulin (microtubules) and inhibits KSP motility by preventing ADP release without altering the release of KSP-ADP complex in microtubules. Ispinesib inhibits the proliferation of a variety of cancer cells, induces apoptosis, and causes tumor regression in vivo. When the Ispinesib and genistein are used in combination, the Ispinesib has stronger growth inhibition effect and apoptosis induction activity, and can also improve the antitumor activity of trastuzumab, lapatinib, doxorubicin and capecitabine.
Surprisingly, the inventors of the present invention found that isflatus is able to activate the re-expression of estrogen receptors, thereby making tumors re-sensitive to less toxic endocrine therapy targeting estrogen receptors. Thus, the aim of inhibiting the growth of breast cancer can be achieved by using endocrine treatment medicines targeting estrogen receptors in combination.
In the above-described uses of the present invention, the employed iostiles are substances having the following structural formula:
the molecular formula of Isatis is C 30 H 33 ClN 4 O 2 Having a molecular weight of 517.06 and having a chemical name of (R) -N- (3-aminopropyl) -N- (1- (3-benzyl-7-chloro-4-oxo-3, 4-dihydroquinazolin-2-yl) -2-methylpropyl) -4-methylbenazemide.
Preferably, in the above-mentioned use of the present invention, isflatus is used for the preparation of a combined anti-triple negative breast cancer drug.
Preferably, in the above-described use of the present invention, islastid is used in combination with a drug targeting an estrogen receptor.
For example, such estrogen receptor-targeting drugs may be endocrine treatment drugs for breast cancer, including but not limited to:
(1) And estrogen: diethylstilbestrol and the like;
(2) And a progestogen: megestrol, and the like;
(3) And anti-estrogen: tamoxifen, toremifene (faretone), traloxifene, and the like;
(4) Aromatase inhibitors: aminoglutethimide, lamatone, runin, exemestane, letrozole, and the like;
(5) Luteinizing hormone-releasing hormone analogs: goserelin, leuprorelin, triptorelin, and the like.
In another aspect, to achieve the objects of the present invention, the present invention provides a composition for inhibiting breast cancer, which can activate the re-expression of estrogen receptor and is combined with a drug targeting estrogen receptor, wherein the composition comprises islastid.
Preferably, the breast cancer against which the above-described composition of the present invention is directed is triple negative breast cancer.
In the above-described composition of the present invention, the employed iostiles are substances having the following structural formula:
in the above composition of the present invention, at least one pharmaceutically acceptable excipient is further included, the excipient is selected from the group consisting of but not limited to: excipient, disintegrant, carrier, sustained-release agent, adhesive, filler, packaging capsule, various processing aids, etc.
Preferably, the above-mentioned composition of the present invention takes the form of oral preparations such as various oral tablets and capsules.
The present inventors have discovered that isflatus enables the re-expression of estrogen receptors, thereby making tumors re-sensitive to less toxic endocrine therapeutic drugs targeting estrogen receptors. Thus, the aim of inhibiting the growth of breast cancer, particularly triple negative breast cancer, can be achieved by using endocrine treatment medicines with lower toxicity in a combined way.
The present invention will be further described with reference to the accompanying drawings and specific embodiments, which are illustrative of certain specific embodiments of the present invention and are not to be construed as limiting the invention.
Drawings
FIG. 1 is a graph comparing the mRNA levels of KIF11 in clinical tissues that are estrogen receptor positive and negative;
FIG. 2 is a graph comparing the mRNA levels of KIF11 in clinical tissues of triple negative breast cancer with non-triple negative breast cancer;
FIG. 3 is a graphical representation of the correlation of KIF11 gene expression with estrogen receptors in clinical tissues;
FIG. 4 is a graph comparing the mRNA levels of KIF11 in clinical tissues that are estrogen receptor negative or positive in the case of progesterone receptor negative or positive;
FIG. 5 is a comparison of KIF11 immunohistochemical staining in pathological sections negative or positive for estrogen receptor;
FIG. 6 is a graph showing the comparison of the mRNA levels of the administered group (Ishes) of BT549 cells and MDA-MB-231 cells with that of a control group, respectively;
FIG. 7 is a schematic Western blot of BT549 cells and MDA-MB-231 cells of each administration group (Ismus) and control group;
FIG. 8 is a graph showing the cell proliferation profiles of MDA-MB-231 cell control group, isens alone group, estrogen alone group, and combination group;
FIG. 9 is a graph showing the cell proliferation profiles of the BT549 cell control group, isens alone group, estrogen alone group, and combination group;
FIG. 10 is a graph showing the cell proliferation profiles of BT549 cell control group, istexas group alone, tamoxifen group alone, and combination group;
FIG. 11 is a graph showing the cell proliferation profiles of MDA-MB-231 cell control group, istexus group alone, tamoxifen group alone, and combination group;
FIG. 12 is a graph showing the growth of MDA-MB-231 tumors in control (NC), istexas alone (ISP), tamoxifen Alone (TAM), and combination (TAM + ISP) nude mice.
Detailed Description
1. Correlation of Estrogen receptor and expression of kinesin superfamily Member 11
(1) bc-GenExMiner 4.5. New mining Module calculates differential Gene expression analysis of breast cancer, results show that protein superfamily member 11 (KIF 11) and Estrogen Receptor (ERA) in clinical database have negative correlation of mRNA and protein levels, and whether the progestogen receptor is negative or positive, the estrogen receptor mRNA expression level is negatively correlated with protein superfamily member 11 (KIF 11); referring to FIGS. 1-4, FIGS. 1-4 show graphs comparing mRNA levels of KIF11 in clinical tissues positive and negative for estrogen receptor, mRNA levels of KIF11 in clinical tissues of triple negative breast cancer and non-triple negative breast cancer, a correlation between gene expression of KIF11 and estrogen receptor in clinical tissues, and mRNA levels of KIF11 in clinical tissues negative or positive for estrogen receptor in the case of negative or positive for progestin receptor, respectively;
(2) Immunohistochemical staining in clinical pathological tissue sections revealed a negative correlation between protein superfamily member 11 (KIF 11) and estrogen receptor (ERa) protein expression levels; please refer to fig. 5, which shows a contrast plot of KIF11 immunohistochemical staining in estrogen receptor negative or positive pathological sections;
it can be seen that the differential gene expression analysis of breast cancer by the novel mining module or the immunohistochemical staining of clinical case sections shows that the expression of estrogen receptor and kinesin superfamily member 11 is in negative correlation.
2. Re-expression of estrogen receptors in triple negative breast cancer cells using the drug epstein, targeted to inhibit kinesin superfamily member 11 (KIF 11):
preparing 10^ -9M Ispinesib culture solution by taking cell culture solution as a solvent, incubating the Ispinesib culture solution for 72 hours respectively for MDA-MB-231 and BT549 triple negative breast cancer cell lines, and then performing protein immunoblotting (Western Blot) and real-time fluorescent quantitative polymerase chain reaction (RT-PCR) on each of the two incubated cells to detect that the estrogen receptor protein level of the cells treated by Ispinesib drugs is increased compared with that of a control group and the messenger ribonucleic acid (mRNA) level of the treated estrogen receptors is increased compared with that of the control group; referring to FIGS. 6 to 7, in which, FIG. 6 is a graph comparing the mRNA levels of the administered group (Ishes) of BT549 cells and MDA-MB-231 cells with that of the control group, respectively; FIG. 7 is a schematic Western blot of BT549 cells and MDA-MB-231 cells of each administration group (Ismus) and control group;
3. isatis (ispinesib) induces triple negative breast cancer cells to re-express estrogen receptors with corresponding functions.
The triple negative breast cancer cells BT549 and MDA-MB-231 are respectively paved into a 96-well plate at a rate of 500/100 ul, after the cells grow adherently, cell culture solution phenol-free RPMI1640, cell culture solution containing 17 beta-estrogen (10 ^ 9M), cell culture solution containing Ispinesib (10 ^ 9M), and combined culture solution of 17 beta-estrogen and Ispinesib are respectively added to be respectively used as a control group, an E2 group, an Ispinesib group and a combined medicine group. Measuring the absorbances at the time points of 0h, 24h, 48h, 72h, 96h and 120h by using a CCK-8 method, and calculating the respective survival rates of the two cells for comparison, wherein the results show that the survival rates of the combined estrogen and the Isatis drug groups of the two cell lines are obviously higher than those of the other three groups at 72h and 96h, and the survival rate of the MDA-MB-231 cells is higher than that of the other three groups at 120 h; referring to FIGS. 8-9, FIG. 8 is a graph showing the cell proliferation of MDA-MB-231 cells in the control group, the Isatis group alone, the estrogen group alone, and the combination group; FIG. 9 is a graph showing the cell proliferation of BT549 cell in a control group, isatis singly used, estrogen singly used and combination group;
4. the estrogen receptor re-expressed by the Isatis induced triple negative breast cancer cells can be inhibited by tamoxifen drugs:
the triple negative breast cancer cells BT549 and MDA-MB-231 are respectively paved into a 96-well plate at a rate of 500/100 ul, after the cells grow adherently, cell culture solution RPMI1640, cell culture solution containing israoxifene (10 ^ 9M), cell culture solution containing 4-hydroxy tamoxifen (10 ^ 7M), cell culture solution containing israoxifene (10 ^ 9M) and 4-hydroxy tamoxifen (10 ^ 7M) are respectively added, and the triple negative breast cancer cells BT549 and the MDA-MB-231 are respectively used as a control group, a single israoxifene group, a single 4-hydroxy tamoxifen group and a combined medicine group. And the CCK-8 method is used for respectively detecting the absorbance at the time points of 0h, 24h, 48h, 72h, 96h and 120h, and the respective survival rates of the two cells are calculated and compared according to the formula of (OD treatment group-OD blank group)/(OD 0h group-OD blank group). The results show that the survival rates of the two cell lines are reduced, and the survival rates of the combined medicine group are lower than those of the control group, the single-use isnow group and the single-use 4-hydroxy tamoxifen group. Referring to fig. 10-11, fig. 10 is a graph showing the cell proliferation of BT549 cells in the control group, islastine alone, tamoxifen alone, and combination group; FIG. 11 is a graph showing the cell proliferation of MDA-MB-231 cell control group, isatis alone, tamoxifen alone, and combination group.
5. Animal tumor formation experiment:
female Balbc/nude mice (Wittinghua) of 4 weeks old were kept in SPF-scale environment for one week, and each nude mouse was subcutaneously injected with 200ul of a cell suspension containing about 1X 10^7 MDA-MB-231 cells at a position of fat pad under the armpit of the nude mouse, and the tumor volume reached 200mm 3 Drug treatment was started and mice were surgically tumor stripped under 1% sodium pentobarbital anesthesia 16 days after treatment or at tumor volumes exceeding 2000mm 3. Tumor volume was measured every 2 days, and volume was calculated as (major diameter x minor diameter ^ 2)/2. Mixing Isatis chinensis with solvent (10% absolute ethanol +10% polyoxyethylene castor oil EL +80%5% glucose injection) to obtain Isatis chinensis solutionInjecting the nude mice intraperitoneally at a dose of 1mg/kg for 4 days (q 4 d), wherein the injection volume is 200ul/25g; the tamoxifen preparation and a solvent (10% absolute ethyl alcohol and 90% corn oil) are prepared into a tamoxifen solution, and the tamoxifen solution is subcutaneously injected into nude mice at a dose of 10mg/kg every day, wherein the injection volume is 250ul/25g. Drug intervention was initiated when tumor volume reached 200mm ^3, control (NC) nude mice injected intraperitoneally with solvent (10% absolute ethanol +10% polyoxyethylene castor oil EL +80%5% glucose injection) and subcutaneously with solvent (10% absolute ethanol +90% corn oil); using Islas solution and subcutaneous injection solvent (10% absolute ethanol +90% corn oil) alone for intraperitoneal injection of Islas group (ISP) nude mice; tamoxifen alone group (TAM) nude mice were injected intraperitoneally with solvent (10% absolute ethanol +10% polyoxyethylated castor oil EL +80% dextrose injection) and subcutaneously with tamoxifen solution; the combination (ISP + TAM) nude mice were injected intraperitoneally with isepath solution and subcutaneously with tamoxifen solution.
The experimental results are as follows: as shown in fig. 12, the tumor growth rate of the combination (ISP + TAM) was slower than that of the control (NC), isnes alone (ISP), and Tamoxifen Alone (TAM), and the tumor growth was delayed as seen from the MDA-MB-231 tumor growth curve; there was no significant change in growth rate between the eosin alone group (ISP) and the tamoxifen alone group (TAM) compared to the control group (NC).
Claims (10)
1. Use of isbanus in the preparation of a combined anti-breast cancer medicament.
2. The use of claim 1, wherein the breast cancer is triple negative breast cancer.
3. The use according to claim 2, wherein the Isatis can activate the re-expression of estrogen receptors.
4. The use according to claim 2, wherein the islastid is in combination with a medicament targeting an estrogen receptor.
5. The use of claim 1, wherein the Isatis is a substance having the formula:
6. a composition for inhibiting breast cancer comprising Isatis, in combination with a drug that targets the estrogen receptor, which activates the re-expression of the estrogen receptor.
7. The composition of claim 6, wherein said breast cancer is triple negative breast cancer.
8. The composition of claim 7 wherein the Isteuss is a substance having the formula:
9. the composition of claim 8, wherein said composition further comprises at least one pharmaceutically acceptable excipient.
10. The composition of claim 9, wherein the composition is in the form of an oral formulation.
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| US20180051346A1 (en) * | 2015-03-17 | 2018-02-22 | Stichting Het Nederlands Kanker Instituut-Antoni van Leeuwenhoek Ziekenhuis | Methods and means for subtyping invasive lobular breast cancer |
Non-Patent Citations (1)
| Title |
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| ARCHANA P. THANKAMONY等: ""Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy"", 《BIOMOLECULES》, vol. 10, no. 9, pages 1 - 15 * |
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