CN110151775B - Application of 17-DMAG in preparation of medicine for inhibiting acute lymphoblastic leukemia of children - Google Patents
Application of 17-DMAG in preparation of medicine for inhibiting acute lymphoblastic leukemia of children Download PDFInfo
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- CN110151775B CN110151775B CN201910584887.6A CN201910584887A CN110151775B CN 110151775 B CN110151775 B CN 110151775B CN 201910584887 A CN201910584887 A CN 201910584887A CN 110151775 B CN110151775 B CN 110151775B
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Abstract
The invention provides application of an Hsp90 inhibitor 17-DMAG in preparation of a medicine for inhibiting acute lymphoblastic leukemia of children, belonging to the technical field of medical biology. Experiments prove that the Hsp90 inhibitor 17-DMAG and cytarabine can synergistically promote the apoptosis of leukemia cells, but the Hsp90 inhibitor and daunorubicin and etoposide cannot achieve similar effects. The method provides a basis for establishing the reasonable application of the chemotherapy scheme of combining 17-DMAG and cytarabine in the children ALL chemotherapy, and provides possibility for improving the chemotherapy effect of leukemia patients and improving drug resistance; and the application of the 17-DMAG and the cytarabine as active ingredients in the children ALL in preparing the medicine for inhibiting the acute lymphoblastic leukemia of the children is proposed for the first time.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to application of an Hsp90 inhibitor 17-DMAG in preparation of a medicine for inhibiting acute lymphoblastic leukemia of children.
Background
Childhood leukemia accounts for the first malignancy in children, Acute Lymphoblastic Leukemia (ALL) accounts for 90% of childhood leukemia, and current treatments for ALL are mainly combined chemotherapy based on risk assessment. However, the high-risk children are very easy to have chemotherapy drug resistance, and some of the middle-risk children have relapse after regular chemotherapy. The treatment after the drug resistance relapse of the children ALL chemotherapy is very troublesome, the complete remission rate of the secondary chemotherapy is obviously reduced, the bone marrow transplantation effect is also unsatisfactory, and the mortality rate of the children is high. Chemotherapy-resistant relapse has long been a bottleneck problem in the treatment of childhood ALL, severely affecting long-term survival. There was no breakthrough progression in the treatment of childhood ALL chemotherapy-resistant relapse.
Heat shock protein 90 (Hsp 90) is overexpressed in children's ALL high-risk group, and it is reported that high expression of Hsp90 in acute leukemia is closely related to disease development and prognosis. Hsp90 inhibitors have a high degree of selective specificity for cancer cells. The Hsp90 inhibitor 17-DMAG (17- [2- (dimethylamino) ethylamino ] -17-desmethylgeldanamycin) has entered phase I clinical trials in adult advanced solid tumors, lymphomas, acute myeloid leukemia, and chronic lymphocytic leukemia as a small molecule targeted drug. However, the application value of 17-DMAG in children's ALL combined chemotherapy is unclear, and the specific action mechanism of the DMAG and first-line chemotherapeutic drug is unclear.
Disclosure of Invention
The invention aims to provide application of an Hsp90 inhibitor 17-DMAG in preparation of a medicine for inhibiting children acute lymphocytic leukemia.
A second object of the present invention is to provide a method of increasing first-line chemotherapeutic killing by combining the Hsp90 inhibitor 17-DMAG with a first-line chemotherapeutic in childhood ALL combination chemotherapy.
Aiming at the defects of the prior art, the invention provides application of an Hsp90 inhibitor 17-DMAG in preparation of a medicine for inhibiting the acute lymphoblastic leukemia of children, and Hsp90 inhibitor 17-DMAG and cytarabine are used as active ingredients in preparation of the medicine for inhibiting the acute lymphoblastic leukemia of children.
A medicine for inhibiting children acute lymphocytic leukemia, which is characterized by comprising 17-DMAG and cytarabine which contain therapeutic quantities of Hsp90 inhibitor and a pharmaceutical carrier or excipient.
The Hsp90 inhibitor 17-DMAG is any pharmaceutically and therapeutically acceptable dosage form, including injection, tablet, capsule, granule, suspension, emulsion, solution, sol, freeze-dried powder injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained release preparation or controlled release preparation, and the preferred dosage form is injection preparation.
Such carriers or excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like as are well known in the art.
The dosage form of the medicament for inhibiting the children acute lymphocytic leukemia is any pharmaceutically and therapeutically acceptable dosage form, and the preferred dosage form is an injection preparation.
The invention provides a method for increasing killing of a first-line chemotherapeutic drug by combining an Hsp90 inhibitor 17-DMAG with the first-line chemotherapeutic drug in children's ALL combined chemotherapy, wherein the first-line chemotherapeutic drug is cytarabine.
The Hsp90 inhibitor 17-DMAG can not only kill leukemia cells with a single drug, but also increase the chemotherapy effect of cytarabine; specifically, 17-DMAG was shown to promote apoptosis in ALL cell lines (Nalm 6 and Reh) and primary leukemic cells from ALL patients (27 cases) as well as cytarabine-induced apoptosis.
The Hsp90 inhibitor, 17-DMAG, when used in combination with daunorubicin or etoposide, does not promote the cell killing effects of daunorubicin and etoposide.
The invention has the beneficial effect.
(1) After the treatment of ALL cell lines (Nalm 6 and Reh) and primary leukemia cells 17-DMAG from ALL patients with drugs, the single drug can induce the apoptosis of the leukemia cells and generate synergistic effect with the combination of cytarabine, so that the chemotherapy effect of cytarabine is greatly improved, but the combined application of the single drug and daunorubicin and etoposide cannot receive similar effect, a basis is provided for the establishment of the reasonable application of a chemotherapy scheme combining 17-DMAG and cytarabine in children ALL chemotherapy, and the possibility is provided for the improvement of the chemotherapy effect of leukemia patients and the improvement of drug resistance.
(2) The invention firstly provides application of 17-DMAG and cytarabine as active ingredients in children ALL in preparing a medicament for inhibiting acute lymphoblastic leukemia of children.
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FIG. 1 is a diagram of the molecular formula of 17-DMAG (17- [2- (dimethylamino) ethylamino ] -17-demethylgeldanamycin).
FIG. 2 is a graph showing that 17-DMAG inhibits the proliferation of ALL cell lines (Nalm 6 and Reh).
FIG. 3 is a graph of 17-DMAG-induced apoptosis of ALL cell line Nalm6 and Reh, in which: FIG. 3-1 is a representative apoptotic result, and FIG. 3-2 is a quantitative statistical chart.
FIG. 4 is a graph of 17-DMAG induced apoptosis of ALL primary cells in which: FIG. 4-1 is a graph of representative primary apoptotic results, and FIG. 4-2 is a quantitative statistical graph
FIG. 5 is a graph of the effect of 17-DMAG on the promotion of chemotherapeutic effect of cytarabine, wherein: FIG. 5-1 is a representative apoptotic result, and FIG. 5-2 is a quantitative statistical chart.
FIG. 6 is a graph of the inability of 17-DMAG to promote the effect of daunorubicin and etoposide chemotherapy.
Detailed Description
The following description of the embodiments refers to the accompanying drawings. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention. The experimental procedures, for which specific conditions are not indicated in the examples, are generally carried out according to conventional conditions, for example as described in Sambrook et al, molecular cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions as recommended by the manufacturer.
Example 1 treatment of leukemia cell lines with different concentrations of 17-DMAG to examine the inhibitory effect on leukemia cell proliferation.
The survival of the cells was examined by treating leukemia cell lines (Nalm 6 and Reh cells) with various concentrations of 17-DMAG (commercial powder in DMSO, formula shown in FIG. 1) at concentrations of 0, 0.01, 0.1, 1, 10, 100. mu.M.
The cell viability assay protocol was: nalm6 and Reh cells were taken in logarithmic growth phase to adjust the concentration to 3X 105The culture medium is inoculated into a 96-well plate, 100 mu L of cell suspension is added into each well, 50 mu L of 17-DMAG is added into each well, the final concentration of the drug in each well is respectively 0.01, 0.1, 1, 10 and 100 mu M, and a DMSO control group and a blank control group only added with the culture medium are simultaneously arranged. Adding 20 mu L MTS after 24h, 48h and 72h, continuously incubating for 4h, measuring the absorbance value of 490nm wavelength by using an enzyme-labeling instrument, taking the average value of the repeated wells, and calculating the cell survival rate according to the survival rate = (the absorbance value of an experimental group-the absorbance value of a blank control group)/(the absorbance value of a control group-the absorbance value of the blank control group) × 100%. All experiments were independently repeated 3 times. The results show leukemia cell proliferationThe colonization was inhibited and the inhibitory effect was significantly dose dependent, see figure 2.
Example 2.17-DMAG (1. mu.M, 10. mu.M) treatment of leukemia cell lines to detect apoptosis-inducing effects.
Leukemia cell lines Nalm6 and Reh cells were resuspended at 3X 105Perml were inoculated in 6-well plates. Leukemia cells were treated with 17-DMAG (1. mu.M, 10. mu.M) while a DMSO control group was set. And after 48 hours, detecting the leukemia cell apoptosis by adopting an Annexin V-FITC/PI method. And (3) treating 27 primary leukemia primary cells derived from the bone marrow of ALL patients for 48 hours by using 17-DMAG 10 mu M, and then detecting the apoptosis condition.
The apoptosis detection scheme is as follows: single cell suspensions were collected, washed twice with cold PBS, 1X 105The cells were resuspended in 300. mu.L of 1 XBinding buffer, 5. mu.L of Annexin V-FITC was added and mixed, 5. mu.L of PI was added after incubation for 15min in the dark at room temperature, incubation for 10min in the dark at room temperature, and flow detection was performed after the staining was completed.
Separating leukemia primary cells by Ficoll-Hypaque density gradient centrifugation method, and culturing the separated primary cells in RPMI 1640 medium containing 20% fetal calf serum, 1% double antibody and 2mM L-glutamine for later use.
The results show that the 17-DMAG induces the apoptosis of the leukemia cell strain, and the apoptosis rate is positively correlated with the drug concentration, which is shown in figure 3. 17-DMAG can induce leukemia cells derived from children patients to apoptosis, and is shown in figure 4.
Example 3.17 Combined treatment of leukemia cell lines with DMAG and Cytarabine experiments.
Nalm6 and Reh cells were resuspended at 3X 105Perml, 10. mu.M of 17-DMAG, cytarabine (Ara-C, 8 nM), and a combination of 17-DMAG and cytarabine were administered and leukemia cell apoptosis was detected after 48h, the apoptosis detection protocol was the same as in example 2. The results show that the apoptosis of the combined treatment group of 17-DMAG and cytarabine is obviously increased and is higher than that of the single-drug treatment group of 17-DMAG and cytarabine, and the result is shown in the attached figure 5.
Example 4.17-DMAG in combination with Etoposide/daunorubicin treatment of Nalm6, Reh cell experiments.
17-DMAG 10 mu M, etoposide (1 uM), daunorubicin (100 nM), and 17-DMAG and etoposide, 17-DMAG and daunorubicin jointly treat Nalm6 and Reh cells for 48h and then detect apoptosis, and the apoptosis detection scheme is the same as that in example 2. The results show that the apoptosis of the combined treatment group of 17-DMAG and two chemotherapeutic drugs is not obviously increased, and the combined treatment group has no synergistic effect compared with the single-drug treatment group of 17-DMAG, etoposide and daunorubicin, and the results are shown in the attached figure 6.
After the ALL cell line (Nalm 6 and Reh) and primary leukemia cells from ALL patients are treated by 17-DMAG drugs in experiments, the finding that not only can the 17-DMAG single drug induce the apoptosis of the leukemia cells, but also the 17-DMAG single drug can be combined with cytarabine to generate a synergistic effect, so that the chemotherapy effect of the cytarabine is improved; however, similar effects cannot be achieved by respectively combining 17-DMAG with daunorubicin and etoposide in the experiment, in other words, the combination of 17-DMAG and daunorubicin and the combination of 17-DMAG and etoposide cannot synergistically induce the apoptosis of leukemia cells. On the basis, a reasonable application of a chemotherapy scheme combining 17-DMAG and cytarabine in children ALL chemotherapy is established, and possibility is provided for improving the chemotherapy effect of leukemia patients and improving drug resistance.
The invention firstly provides application of 17-DMAG and cytarabine as active ingredients in children ALL in preparing a medicament for inhibiting acute lymphoblastic leukemia of children.
Claims (1)
1. The application of an Hsp90 inhibitor 17-DMAG and cytarabine as active ingredients in the preparation of a medicine for inhibiting the acute lymphoblastic leukemia of children is characterized in that the Hsp90 inhibitor 17-DMAG can promote the apoptosis of the leukemia cells and promote the apoptosis induced by cytarabine; the leukemia cell is Nalm6 or Reh cell line.
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| CN109045042A (en) * | 2018-09-21 | 2018-12-21 | 上海交通大学医学院附属上海儿童医学中心 | Application of the ATM inhibitor in the drug that preparation inhibits acute lymphatic leukemia recurrence |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109045042A (en) * | 2018-09-21 | 2018-12-21 | 上海交通大学医学院附属上海儿童医学中心 | Application of the ATM inhibitor in the drug that preparation inhibits acute lymphatic leukemia recurrence |
Non-Patent Citations (2)
| Title |
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| Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pediatric Acute Lymphoblastic Leukemia (ALL) with Respect to Bcr-Abl Status and Imatinib Mesylate Sensitivity;Effects of 17-Allylamino-17-Demethoxygeldanamycin (17-AAG) on Pe;《PEDIATRIC RESEARCH》;20050119;第57卷(第3期);参见摘要和表1 * |
| HSP90 抑制剂 17-DMAG 对急性淋巴细胞白血病Jurkat 细胞株增殖和凋亡的影响;葛芳芳等;《中国实验血液学杂志》;20170430;第25卷(第4期);参见讨论部分 * |
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