CN109833327A - A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell - Google Patents
A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell Download PDFInfo
- Publication number
- CN109833327A CN109833327A CN201711213603.XA CN201711213603A CN109833327A CN 109833327 A CN109833327 A CN 109833327A CN 201711213603 A CN201711213603 A CN 201711213603A CN 109833327 A CN109833327 A CN 109833327A
- Authority
- CN
- China
- Prior art keywords
- gemcitabine
- bladder cancer
- cell
- drug
- chemotherapeutics
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses PP2A inhibitor LB100 and chemotherapeutics Gemcitabine synergy is able to suppress the growth of bladder cancer tumour cell.The method specifically used is the agent-feeding treatment that the bladder cancer cells such as T-24, RT-4 are carried out with different time and concentration gradient, then carries out cell viability detection, and LB100, which is added, in discovery can be improved Gemcitabine to the drug susceptibility of bladder cancer cell.Meanwhile internal mouse tumor formation experiment confirms that two kinds of drug combinations of LB100 and Gemcitabine can obviously inhibit the growth of tumour.Therefore, clinically the combination of two kinds of drugs can achieve the purpose that effectively to treat bladder cancer.
Description
Technical field
It is thin to bladder cancer present invention relates solely to chemotherapeutics Gemcitabine is increased with PP2A inhibitors of phosphatases LB100
The sensibility of born of the same parents belongs to cell biology and field of medical technology to achieve the purpose that treat bladder cancer.
Background technique
Bladder cancer is the most common malignant tumour of urinary system, and disease incidence occupies the first place of urinary system malignant tumour.In recent years
Carry out its disease incidence and the trend constantly increased is presented.Clinically 70% or so bladder cancer patients make a definite diagnosis Shi Weifei Myometrial involvement Guang
Cancer (nonmuscle invasive bladder cancer, NMIBC), primary treatments are bladder tumor electricity
Art (transurethral resection of bladder tumor, TUR-Bt) is cut, but Postoperative recurrent rate height is to lead to hand
The main reason for art treatment failure.However, the patient of TURBT postoperative 70% or so has tumor recurrence, and there is 25% patient
Development is Myometrial involvement bladder cancer after recurrence.It is the main of bladder cancer death that grade malignancy, which increases, after postoperative easy to recur and recurrence
Reason, the most effective method for preventing NMIBC patient's postoperative recurrence and progress at present are aided with irrigation of bladder and exempt from TUR-Bt is postoperative
Epidemic disease inhibitor or chemotherapeutics.Common intravesical chemotherapy and immunotherapy medicaments include cis-platinum (cisplatin), mitomycin
C (mitomycin C), BCG vaccine (BacillusCalmette-Guerin, BCG), interferon-' alpha ' etc..Although irrigation of bladder and
Chemotherapeutics in short term have certain curative effect, but these method offer limited effectiveness and have serious local damage and whole body poison
Side effect such as hemorrhagic cystitis, hematopoiesis and immunological function repression etc., have severely impacted the quality of life of patient.In view of current
The unstability and its significant toxic side effect of bladder cancer dabbling drug and chemotherapeutical medicine curative effect.Therefore, it finds safe and effective
Bladder cancer treatment drug have become therapeutic field of tumor research hot and difficult issue.
Protein phosphatase 2 (PP2A) is a kind of main serine and Threonine Phosphatases, it is by being catalyzed
Subunit, Structural subunits adjust subunit tripolymer composition.Structural subunits there are two homology isomers of PPP2R1A and PPP2R1A,
There are two homology isomers of PPP2CA and PPP2CB for catalytic subunit, and adjust subunit there are many homology isomers, are divided into
Four families, adjusting subunit in different cell line is to have differences, but they have one section of conserved sequence in C-terminal.
PP2A is a kind of multi-functional enzyme, and substrate is numerous intracorporal transcription factors and protein kinase;Yeast, drosophila and the animal of mouse
In the research of model it has been found that PP2A take part in DNA replication dna, gene expression, the cell cycle, cell metabolism, cell differentiation and
A series of cellular activity processes such as apoptosis, at the same it again in the cascade reaction of signal transduction with other phosphorylases and kinases phase
Interaction constitutes the transduction for adjusting macromolecular regulation downstream signal.Catalytic subunit activity mainly by post-transcriptional level phosphorylation and
The condition regulation of methylation.Particular, it is important that many laboratory research discoveries, PP2A can be used as one of drug in recent years
Target inactivates its catalytic subunit phosphorylation or demethylation by small molecule compound or endogenous inhibitor, to reach
To killer's tumour cell, stablize the purpose of tumour.Gemcitabine is as clinical broad-spectrum anti-cancer drug and bladder cancer clinic one
Line anticancer drug, has a better effect Advanced Carcinoma Patient, but in a short time, and human body can generate strong drug resistance.At present
Gemcitabine joint cisplatin is high-efficient to treat advanced stage urothelial cancer, and adverse reaction is tolerable.Although
Cisplatin can reduce cell to the drug resistance of gemcitabine, but use while two kinds of chemotherapeutics, will increase
The pressure of liver, side effects on the body are obvious.
Summary of the invention
The present invention relates to the new discoveries of the drug for the treatment of bladder tumor, it is therefore an objective to provide phosphoprotein phosphatase PP2A inhibitor
The collective effect of LB100 and chemotherapeutics gemcitabine are to the inhibiting effect of bladder cancer tumour cell, to reach collaboration
The effect of gemcitabine treatment bladder cancer.
PP2A inhibitor LB100 is used in cancer of pancreas, oophoroma and breast cancer with chemotherapeutics sensitizer,
There is preferable effect of enhanced sensitivity.We have discovered that LB100 not only can increase bladder cancer cell to the sensibility of chemotherapeutics, also
Bladder cancer cell can be reversed to the drug resistance of gemcitabine.Further, it has been found that LB100 is used alone, can result in bladder
Cancer cell DNA damage can preferably inhibit the growth of bladder cancer in vivo.Moreover, LB100 is to human body in doses
Toxicity is little.It is believed that LB100 is likely to become the effective chemotherapeutics of clinical potential low toxicity and sensitizer, therefore, Wo Menxu
Further investigate mechanism of action of the LB100 in bladder cancer cell.LB100 and gemcitabine combination can reach better
The effect for treating bladder cancer.
Detailed description of the invention
Fig. 1 is that control group, Dan Jia gemcitabine (Gem) (0.5,1,5 μM) and same concentrations are respectively set
Gemcitabine combines (5 μM) processing bladder cancer cell T-24 of LB100, cell viability testing result figure after 24h.
Fig. 2, which is that T-24 cell is single respectively, adds 0.5 μM of gemcitabine and 5 μM of LB100 and gemcitabine to join
After being handled 24 hours under the conditions of conjunction LB100, cell pyrolysis liquid is collected, is tested by western blot, with Apoptosis correlation
Albumen carries out detection schematic diagram.
Fig. 3 is that T-24 cell expands culture, and is fixed with matrigel, carries out back of mice two sides kind tumor.It establishes naked
After mouse Transplanted tumor model, mouse is divided into four groups, every component 5, one group, as control, is in addition used for three groups respectively
Gemcitabine and LB100 is individually handled and two medication combined processing, the big logotype after tumor resection.
Fig. 4 is that T-24 cell expands culture, and is fixed with matrigel, carries out back of mice two sides kind tumor.It establishes naked
After mouse Transplanted tumor model, mouse is divided into four groups, every component 5, one group, as control, is in addition used for three groups respectively
Gemcitabine and LB100 is individually handled and the volume growth curve of the tumour of two medication combined processing.
Fig. 5 is that T-24 cell expands culture, and is fixed with matrigel, carries out back of mice two sides kind tumor.It establishes naked
After mouse Transplanted tumor model, mouse is divided into four groups, every component 5, one group, as control, is in addition used for three groups respectively
Gemcitabine and LB100 is individually handled and two medication combined processing.Inject drug concentration: gemcitabine-
2.5mg/kg, LB100-1.5mg/kg, the weight of tumour after processing.
Specific embodiment
Now in conjunction with example, the present invention will be further described.Example is only limitted to illustrate the present invention, rather than to limit of the invention
It is fixed.
It is prepared by the solution of embodiment 1PP2A protein phosphatase inhibitor LB100 and chemotherapeutic gemcitabine.
It is 10mM that LB100, which is prepared into storing liquid concentration with PBS dissolution,.LB100 adds the DMEM culture medium containing 10%FBS dilute
It releases to 1mM as working concentration.It is 50mM that Gemcitabine, which is prepared into storing liquid concentration with DMSO dissolution, and gemcitabine adds
The DMEM culture medium for containing 10%FBS is diluted to 500uM as working concentration.
Inhibiting effect of the synergy of embodiment 2PP2A inhibitor and LB100 to bladder cancer cell.
T-24 cell is taped against in 96 orifice plates, is divided into 7 groups, respectively control group, tri- kinds of Dan Jia 0.5,1,5uM concentration
Tri- groups of gemcitabine, be used in combination respectively with LB100 (5uM) three groups of three kinds of concentration gemcitabine, every group of setting three
A parallel control carries out cell viability detection with Cell Titer Glo cytoactive detection kit after processing 24 hours, examines
Survey instrument living cells imager.Its result is as shown in Figure 1, gemcitabine joint LB100 can effectively inhibit bladder cancer
The proliferation of cell.
3 phosphoprotein phosphatase PP2A inhibitor LB100 of embodiment leads to DNA damage and promotes the apoptosis of bladder cancer cell.
T-24 cell is taped against in 6cm ware, is divided into 4 groups, respectively control group, Dan Jia gemcitabine, Dan Jia LB100,
LB100 joint gemcitabine collects cell protein after agent-feeding treatment 24 hours, is examined using western blot experiment
It surveys.Its result can promote the DNA damage of bladder cancer cell as shown in Fig. 2, when singly adding LB100;?
Gemcitabine combines under LB100 processing, compared with the apoptosis of the single plus gemcitabine promotion bladder cancer cell that can have been reached.
The LB100 joint gemcitabine in nude mouse of embodiment 4 can effectively inhibit the growth of bladder cancer.
T-24 cell is expanded culture, is fixed with matrigel, back of mice two sides kind tumor, the plantation of each tumor are carried out
5x105A cell is mixed with the matrigel of 200ul.After establishing Nude Mouse Model, mouse is divided into four groups, every component 5
Only, one group as control, in addition uses gemcitabine and LB100 individually to handle and two medication combined processing respectively for three groups.
Inject drug concentration: gemcitabine-2.5mg/kg, LB100-1.5mg/kg use physiological saline solution respectively.Pass through abdominal cavity
By in drug injection to Mice Body, 25mm is grown to tumour3When left and right, drug-treated is carried out, every other day drug-treated
Once, the volume of measurement tumour, final result are as shown in Figure 4 every time.After 17 periods, tumour is taken out from back of mice,
Weigh its weight, final result such as Fig. 5, tumor size is as shown in Figure 3.From the experimental results showed that, in Mice Body, LB100 connection
The growth of tumour can effectively be inhibited by closing gemcitabine.
Show that LB100 can not only lead to DNA damage by above-mentioned experiment, and combine gemcitabine can effectively press down
The growth of bladder cancer processed, therefore, the inhibitor LB100 of PP2A can make bladder cancer cell sensitive to gemcitabine, so as to
Enough achieve the purpose that treat bladder cancer.
Claims (5)
1. a kind of medicinal mixture, including phosphoprotein phosphatase PP2A inhibitor LB100 and chemotherapeutics gemcitabine.
2. medicinal mixture according to claim 1, it is characterised in that: the compound a is phosphoprotein phosphatase PP2A inhibition
Agent LB100, structural formula of compound are (a);The compound b is chemotherapeutics gemcitabine, and structural formula of compound is
(b);
3. medicinal mixture according to claim 1, it is characterised in that: the mass ratio of gemcitabine and LB100 be 4~
5:2~3, preferably 5:2.
4. a kind of application of any medicinal mixture of claim 1-3 in preparation treatment bladder cancer drug.
5. application according to claim 4, it is characterised in that: the drug is injection drug, and gemcitabine injects medicine
Object concentration is 2.5~5mg/kg, preferably 2.5mg/kg;LB100 injects 1~2mg/kg of drug concentration, preferably 1.5mg/kg.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711213603.XA CN109833327A (en) | 2017-11-28 | 2017-11-28 | A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201711213603.XA CN109833327A (en) | 2017-11-28 | 2017-11-28 | A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109833327A true CN109833327A (en) | 2019-06-04 |
Family
ID=66880865
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201711213603.XA Pending CN109833327A (en) | 2017-11-28 | 2017-11-28 | A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109833327A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114181906A (en) * | 2021-12-10 | 2022-03-15 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer gemcitabine drug-resistant cell strain and application thereof |
WO2022232135A1 (en) * | 2021-04-28 | 2022-11-03 | The University Of Toledo | Methods of treating cancer and ischemia diseases by inhibition and intervention of atr prolyl isomerization |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107072991A (en) * | 2014-09-12 | 2017-08-18 | 莱克斯特生物技术公司 | Mankind's administration of inhibitors of phosphatases |
-
2017
- 2017-11-28 CN CN201711213603.XA patent/CN109833327A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107072991A (en) * | 2014-09-12 | 2017-08-18 | 莱克斯特生物技术公司 | Mankind's administration of inhibitors of phosphatases |
Non-Patent Citations (1)
Title |
---|
CHRISTOPHER S HONG等: "LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential", 《CANCER BIOLOGY & THERAPY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022232135A1 (en) * | 2021-04-28 | 2022-11-03 | The University Of Toledo | Methods of treating cancer and ischemia diseases by inhibition and intervention of atr prolyl isomerization |
CN114181906A (en) * | 2021-12-10 | 2022-03-15 | 深圳市第二人民医院(深圳市转化医学研究院) | Human bladder cancer gemcitabine drug-resistant cell strain and application thereof |
CN114181906B (en) * | 2021-12-10 | 2023-10-13 | 深圳市第二人民医院(深圳市转化医学研究院) | Gemcitabine resistant cell line for human bladder cancer and application thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Gong et al. | The role of necroptosis in cancer biology and therapy | |
Sun et al. | Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m6A signaling | |
Ma et al. | Anemoside B4 prevents acute ulcerative colitis through inhibiting of TLR4/NF-κB/MAPK signaling pathway | |
WO2016062287A1 (en) | Uses of cellcept in preparing cancer-inhibiting pharmaceutical composition | |
Chen et al. | Synergistic interactions between sorafenib and bortezomib in hepatocellular carcinoma involve PP2A-dependent Akt inactivation | |
Zhang et al. | Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway | |
Feng et al. | Luteolin, an aryl hydrocarbon receptor ligand, suppresses tumor metastasis in vitro and in vivo | |
Lin et al. | Tanshinone IIA enhances the effects of TRAIL by downregulating survivin in human ovarian carcinoma cells | |
Sun et al. | Roles of p38 and JNK protein kinase pathways activated by compound cantharidin capsules containing serum on proliferation inhibition and apoptosis of human gastric cancer cell line | |
Guo et al. | (-)-β-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity | |
Maleki et al. | Multiple interactions between melatonin and non‐coding RNAs in cancer biology | |
Jiang et al. | Ligustilide inhibits the proliferation of non-small cell lung cancer via glycolytic metabolism | |
Yang et al. | Cinobufagin restrains the growth and triggers DNA damage of human hepatocellular carcinoma cells via proteasome-dependent degradation of thymidylate synthase | |
CN109833327A (en) | A kind of chemotherapeutics Gemcitabine that increases is to the pharmaceutical composition of the sensibility of bladder cancer cell | |
Chen et al. | Sini decoction inhibits tumor progression and enhances the anti-tumor immune response in a murine model of colon cancer | |
Qin et al. | Combination of dendrobium mixture and metformin curbs the development and progression of diabetic cardiomyopathy by targeting the lncRNA NEAT1 | |
Ke et al. | Mollugin induced oxidative DNA damage via up-regulating ROS that caused cell cycle arrest in hepatoma cells | |
Chen et al. | JNK molecule is a toxic target for IPEC-J2 cell barrier damage induced by T-2 toxin | |
Hao et al. | Scutebarbatine A induces ROS-mediated DNA damage and apoptosis in breast cancer cells by modulating MAPK and EGFR/Akt signaling pathway | |
Tan et al. | Erchen Plus Huiyanzhuyu Decoction Inhibits the Growth of Laryngeal Carcinoma in a Mouse Model of Phlegm‐Coagulation‐Blood‐Stasis Syndrome via the STAT3/Cyclin D1 Pathway | |
Zhao et al. | Distinct EphB4-mediated mechanisms of apoptotic and resistance to dasatinib in human chronic myeloid leukemia and K562 cell lines | |
Yang et al. | Fuzheng Jiedu decoction induces apoptosis and enhances cisplatin efficacy in ovarian cancer cells in vitro and in vivo through inhibiting the PI3K/AKT/mTOR/NF‐κB signaling pathway | |
WO2020181802A1 (en) | Effective anti-malignant tumor rpharmaceutical composition and application thereof | |
Shi et al. | Natural products targeting the MAPK-signaling pathway in cancer: overview | |
Sun et al. | The role of phosphatidylinositol 3-kinase signaling pathways in pancreatic cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190604 |
|
RJ01 | Rejection of invention patent application after publication |