CN109908144B - Application of isoliensinine in preparation of drugs for targeted inhibition of AKT activation - Google Patents
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Abstract
The invention discloses an application of isoliensinine in preparation of a medicine for targeted inhibition of AKT activation, and researches show that after cervical cancer cells are treated by isoliensinine, AKT activation is obviously inhibited, isoliensinine inhibits an AKT activation channel, p21 expression is up-regulated, Cyclin E1 and Cyclin-dependent kinase CDK2 expression are down-regulated, so that the cell cycle of the cervical cancer cells is retarded in the G1 stage, and finally, the proliferation and migration of the cervical cancer cells are inhibited and apoptosis is induced; the invention provides a new medical application of the isoliensinine, provides a new candidate drug for treating cervical cancer and has important clinical significance.
Description
Technical Field
The invention relates to the field of biological medicines, and particularly relates to application of isoliensinine in preparation of a medicine for targeted inhibition of AKT activation.
Background
AKT, also known as Protein Kinase B (PKB), is activated excessively in cells, leading to a constant flow of cellular matrix through the glycolytic pathway, which leads to altered cell biological behavior. There are two pathways for its activation, one is the phosphorylation pathway (pAKT) and the other is the methylation pathway.
AKT is used as a target point of various tumor carcinogenic activation, and has key influence on the aspects of tumor cell proliferation, migration, autophagy and apoptosis. Therefore, effective control of AKT activation is crucial for drug treatment and prognosis in tumor patients.
Several anti-tumor AKT inhibitors have been successfully developed in the market today, but these inhibitors suffer from problems of limited pharmacokinetics, cell tolerance and efficacy. The endogenous AKT inhibitor with definite curative effect and small toxic and side effects on cells is a new direction for developing future AKT inhibitors.
Isoliensinine (Isoliensinine, ISO) is an endogenous bisbenzylisoquinoline alkaloid extracted and separated from plumula Nelumbinis (plumula Nelumbinis) of mature seed of Nymphaea plant (figure 1). Isoliensinine as an endogenous effective component of Chinese herbal medicines has wide pharmacological effects, and has been reported to have potential antiviral and anticancer activities. Recent studies have shown that isoliensinine: (1) in cervical cancer cells, inducing autophagy; (2) in liver cancer cells, apoptosis is induced; (3) in breast cancer cells, apoptosis is induced and cell proliferation is inhibited.
Disclosure of Invention
In view of the above, an object of the present invention is to provide an application of isoliensinine in preparing a drug for targeted inhibition of AKT activation; the invention also aims to provide the application of the isoliensinine in preparing the medicine for treating the cervical cancer.
In order to achieve the purpose, the invention provides the following technical scheme:
1. application of isoliensinine in preparing medicine for inhibiting AKT activation in targeted manner is provided.
The application of the isoliensinine in the medicine for inhibiting AKT activation in a targeted mode is preferably that the effective dose is 5-80 mu M.
2. Application of isoliensinine in preparing medicine for treating cervical cancer is provided.
As a preferred technical scheme, the cervical cancer is one or more of cervical cancer cells SiHa, HeLa, C33A or CaSki.
As a preferable technical scheme, the isoliensinine is applied to preparation of a medicine for inhibiting the activity of cervical cancer cells.
As a preferable technical scheme of the invention, the isoliensinine is applied to the preparation of the medicine for inhibiting the proliferation of the cervical cancer cells.
As a preferable technical scheme, the isoliensinine is applied to preparation of a medicine for inhibiting migration of cervical cancer cells.
As a preferred technical scheme, the isoliensinine is applied to preparation of a medicine for inhibiting apoptosis of cervical cancer cells.
The invention has the beneficial effects that: the invention provides a medicine for inhibiting AKT activation anti-cervical cancer proliferation, migration and apoptosis induction by targeting isoliensinine serving as a plant endogenous bioactive component, widens the medical application of isoliensinine, provides a new choice for improving the survival prognosis of cervical cancer patients, and has important clinical significance for treating late-stage cervical cancer.
Drawings
In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:
FIG. 1 shows the chemical formula of Isoliensinine (ISO).
FIG. 2 shows the activation targeting inhibition of Isoliensinine (ISO) on cervical carcinoma AKT (pAKT) (A: SiHa, B: C33A, C: CaSki and D: HeLa).
FIG. 3 shows the inhibitory effect of Isoliensinine (ISO) on the viability of cervical cancer cells (A: SiHa, B: C33A, C: CaSki and D: HeLa,: p <0.05, #: p <0.01, 24h and 48 h).
FIG. 4 shows the inhibition of SiHa cell proliferation for cervical cancer by Isoliensinine (ISO) (#: p <0.01, SiHa, 24 h).
FIG. 5 shows the inhibition of cervical cancer C33A cell proliferation by Isoliensinine (ISO) (#: p <0.01, C33A, 24 h).
FIG. 6 shows the inhibition of cervical carcinoma CaSki cell proliferation by Isoliensinine (ISO) (#: p <0.01, CaSki, 24 h).
FIG. 7 shows the inhibition of cervical cancer HeLa cell proliferation by Isoliensinine (ISO) (#: p <0.01, HeLa, 24 h).
FIG. 8 shows RNA expression regulation of cervical cancer C33A, CaSki and HeLa cell cycle-related proteins p21, Cyclin E1 and CDK2 by Isoliensinine (ISO) (C33A, CaSki and HeLa, 24 h).
FIG. 9 shows the protein expression modulating effects of Isoliensinine (ISO) on cervical cancer C33A, CaSki and HeLa cell cycle-related proteins p21, Cyclin E1 and CDK2 (C33A, CaSki and SiHa, 24 h).
FIG. 10 is a graph of the inhibition of cell migration of cervical carcinoma CaSki by Isoliensinine (ISO) (CaSki, 24h and 48 h).
FIG. 11 shows the induction of apoptosis of CaSki cells in cervical cancer by Isoliensinine (ISO) (CaSki, 48 h).
FIG. 12 shows the induction of apoptosis of cervical carcinoma C33A by Isoliensinine (ISO) (C33A, 48 h).
Fig. 13 is a graph of the mechanism of targeting inhibition of AKT activation of cervical cancer proliferation, migration and apoptosis induction by Isoliensinine (ISO).
Detailed Description
The present invention is further described with reference to the following drawings and specific examples so that those skilled in the art can better understand the present invention and can practice the present invention, but the examples are not intended to limit the present invention.
The isoliensinine used in the invention can be purchased from Chinese food and drug testing research institute, and can also be purchased from commercial companies (such as SIGMA company, etc.), and the chemical structural formula of the isoliensinine is shown in figure 1.
Example 1 inhibition of cervical cancer AKT (pAKT) activation by Isoliensinine
Respectively culturing cervical cancer SiHa, C33A, CaSki and HeLa cells, collecting cells when the cells grow to logarithmic phase, digesting with trypsin, neutralizing with complete culture medium, and adjusting cell suspension concentration to 1 × 105one/mL, the cell suspensions were seeded into 96-well plates, 180. mu.L per well, and Isoliensine (ISO) was added to SiHa, C33A, CaSki and HeLa cells at concentrations of 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M, respectively, for 24 h. The Western blot method for detecting the protein expression of the cervical cancer cell pAKT (Ser 473 phosphorylation) is as follows:
(1) assembling electrophoresis tank, checking leakage, preparing different separation gel according to requirement, adding concentrated gel after solidification, and solidifying for 30 min.
(2) Adding electrophoresis buffer solution into the electrophoresis tank, vertically pulling out the sample application comb, extracting target gene protein sample, concentrating gel at 80V for 30min, and separating gel at 120V for 90 min.
(3) Film transfer: soaking the PDVF membrane in methanol for about 1min, taking out the glass plate, removing concentrated glue, removing redundant glue, and performing constant-current membrane conversion at 100mA for 90-240 min.
(4) Blocking with 3% skimmed milk powder for 60min, washing with PBS-T for 10min, incubating with primary antibody (pAKT), standing overnight at 4 deg.C, recovering primary antibody, washing with PBS-T shaking table for 3 times, 10min each time, incubating with rabbit secondary antibody for 90min, and washing with PBS-T for 3 times, 10min each time.
(5) Tabletting and developing.
The detection result is shown in figure 2, when isoliensinine is used for treating cervical cancer cells under the condition of higher than 10 mu M, the activation of pAKT (Ser 473 phosphorylation) is reduced, and the activation inhibition of pAKT (Ser 473 phosphorylation) is more obvious along with the increase of the concentration of isoliensinine.
Example 2 inhibition of Isoliensinine on cervical cancer cell viability
Cervical cancer SiHa, C33A, CaSki and HeLa cells were treated with Isoliensinine (ISO) according to the method of example 1, and the viability of the cervical cancer cells was measured using the CCK8 method as follows:
(1) inoculating 5000-10000 cells into a 96-well plate, and inoculating 5% CO at 37 DEG C2Culturing;
(2) cells were incubated for 24h and 48h after adherence with isoliensinine at 0. mu.M, 5. mu.M, 10. mu.M, 15. mu.M, 20. mu.M and 25. mu.M and blank with equal volume of DMSO as controls.
(3) Discard the medium, add pre-mixed CCK8 (10%) medium at 37 deg.C, 5% CO2And incubating for 1-2 h.
(4) OD value at 450nm of microplate reader.
As shown in FIG. 3, the activity of the SiHa, C33A, CaSki and HeLa cells of the cervical cancer cells gradually decreased with the increase of the isoliensinine treatment concentration or the increase of the treatment time.
Example 3 inhibition of proliferation of cervical cancer cells by Isoliensinine
(1) Inhibition of cervical cancer SiHa, C33A, CaSki and HeLa cell proliferation by isoliensinine
Cervical cancer SiHa, C33A, CaSki and HeLa cells were treated with Isoliensinine (ISO) at concentrations of 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M as described above and the cell cycle was measured by flow method as follows:
a. taking cells 1X 106The cells/mL were plated in 6-well plates and after attachment were added isoliensinine at 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M and blank plus equal volume of DMSO at 37 ℃ with 5% CO as control2And culturing for 24 h.
b, centrifuging at 2000rpm for 5min, collecting cells in an EP tube, adding 300 mu L of precooled PBS to resuspend the cells, adding 700 mu L of absolute ethyl alcohol, mixing uniformly, and fixing at 4 ℃ overnight. After ethanol fixation, the mixture is centrifuged at 2000rpm for 5min, ethanol is removed, PBS is added for washing, and the mixture is centrifuged at 2000rpm for 5 min.
c. PBS was removed, 200. mu.L of PBS and 2. mu.L of RNase (0.25mg/mL) were added (incubation at 37 ℃ C. for 30min), and 0.5mL of 50. mu.g/mL PI solution was added and the mixture was stained in the dark at room temperature for 30 min.
d. And starting up and detecting.
The results are shown in fig. 4-7, the cell proliferation is retarded in the cell cycle G1, which indicates that the cervical cancer cell proliferation is obviously inhibited after the cervical cancer SiHa, C33A, CaSki and HeLa cells are treated by isoliensinine.
(2) Regulation of RNA expression by isoliensinine on cervical cancer cell cycle-associated regulatory protein p21, Cyclin E1 and Cyclin-dependent kinase CDK2
Cervical cancer C33A, CaSki and HeLa cells were treated with Isoliensinine (ISO) at concentrations of 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M as described above and the QRT-PCR was used to measure the RNA expression of cell cycle-associated regulatory proteins as follows:
a. collecting drug-treated cervical cancer cells, adding 0.5mL Trizol into each tube, repeatedly blowing, dissolving cells, transferring liquid into an EP tube without RNase, adding 200 μ L chloroform, violently shaking, standing for 5min, 12000rpm, centrifuging at 4 deg.C for 15 min.
b. The upper aqueous phase was transferred to another new EP tube, 200. mu.L of isopropanol was added, gently shaken, allowed to stand for 10min at 12000rpm, 4 ℃ and centrifuged for 15 min.
c. Discard the supernatant, centrifuge instantaneously, aspirate excess supernatant, add 20 μ L of DEPC water to dissolve RNA. Taking 5 mu L of RNA, 1 mu L of oligo (dT) random primer and 6 mu L of DEPC water, mixing uniformly, performing instant centrifugation, and synthesizing a first strand by a PCR instrument.
d.5min later, placing on ice, sequentially adding 5 xbuffer 4 μ L, RNase inhibitor 1 μ L, dNTP2 μ L, reverse transcriptase 1 μ L, and total 20 μ L, mixing, centrifuging instantly, and synthesizing the second chain.
e.PCR reaction: 2 Xmix 10 μ L, cDNA template 1 μ L, primer 2 μ L, sterilized triple distilled water 7 μ L, total 20 μ L system, mixing, instant centrifuging, and loading on machine.
f. Preparing 1-2% agarose gel and performing electrophoresis.
g. Diluting cDNA by 100 times, preparing qPCR reaction system, Mix10 uL (cell cycle related regulatory protein) primer 2 uL, cDNA template 5 uL, H2Adding O into 20 μ L system of 3 μ L, mixing, centrifuging instantly, and processing.
The detection results are shown in fig. 8, isoliensinine up-regulates the RNA expression of p21, and down-regulates the RNA expression of Cyclin E1 and Cyclin-dependent kinase CDK 2.
(3) Regulation effect of isoliensinine on expression of cervical cancer cell cycle-related regulatory protein p21, Cyclin E1 and Cyclin-dependent kinase CDK2 protein
Cervical cancer C33A, CaSki and HeLa cells were treated with Isoliensinine (ISO) at concentrations of 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M according to the above method, and protein expression of the cervical cancer cell cycle-associated regulatory protein was detected by Western blot method as follows:
(1) assembling electrophoresis tank, checking leakage, preparing different separation gel according to requirement, adding concentrated gel after solidification, and solidifying for 30 min.
(2) Adding electrophoresis buffer solution into the electrophoresis tank, vertically pulling out the sample application comb, extracting target gene protein sample, concentrating gel at 80V for 30min, and separating gel at 120V for 90 min.
(3) Film transfer: soaking the PDVF membrane in methanol for about 1min, taking out the glass plate, removing concentrated glue, removing redundant glue, and performing constant-current membrane conversion at 100mA for 90-240 min.
(4) Blocking with 3% skimmed milk powder for 60min, washing with PBS-T for 10min, incubating with primary antibody (pAKT), standing overnight at 4 deg.C, recovering primary antibody, washing with PBS-T shaking table for 3 times, 10min each time, incubating with rabbit secondary antibody for 90min, and washing with PBS-T for 3 times, 10min each time.
(5) Tabletting and developing.
The detection result is shown in fig. 9, isoliensinine up-regulates protein expression of p21, and down-regulates protein expression of Cyclin E1 and Cyclin-dependent kinase CDK 2.
Example 4 inhibition of migration of cervical cancer cells by Isoliensinine
Cervical cancer CaSki cells are treated by Isoliensinine (ISO) with the concentrations of 20 muM, 40 muM and 80 muM according to the method, and the inhibition effect of isoliensinine on cervical cancer cell migration is detected by a scratch experiment, and the method comprises the following specific steps:
(1) the cells of the same group are respectively 1 × 106Individual cells/well were seeded in 6-well plates;
(2) when the cells are cultured to a monolayer confluence state, carrying out cell synchronization for 24h by using a DMEM culture solution containing 1% FBS;
(3) and lightly scratching the cell layer in the vertical direction of the culture plate by using the tip of a 10-microliter sterile pipetting head to form a cell-free scratch area with the width of 300-500 mu m.
(4) Adding isoliensinine at 20. mu.M, isoliensinine at 40. mu.M and isovolumetric DMSO in blank as negative control group, and TGF-beta 1 as positive control group.
(5) The pictures are taken under a microscope for 0h, 24h and 48 h.
The detection result is shown in fig. 10, compared with the negative control group, the positive TGF-beta 1 control group has the effect of promoting migration of CaSki of cervical cancer, compared with the ISO group, the TGF-beta 1+ ISO group is basically consistent in width, and Isoliensinine (ISO) obviously inhibits migration of CaSki.
Example 5 Induction of apoptosis in cervical cancer cells by Isoliensinine
Flow-type detection of Isoliensinine (ISO) for inducing apoptosis of cervical cancer cells (CaSki and C33A), treating the cervical cancer CaSki and C33A cells with isoliensinine at concentrations of 0. mu.M, 5. mu.M, 10. mu.M, 20. mu.M, 30. mu.M and 40. mu.M according to the above method, specifically comprising the following steps:
(1) taking cells 1X 106Inoculating each cell/mL into 6-well plate, adding isoliensinine at 0 μ M, 5 μ M, 10 μ M, 20 μ M, 30 μ M, and 40 μ M after adherence, blank adding equal volume of DMSO as control, 37 deg.C, 5% CO2Culturing for 48 h.
(2) Trypsinized, centrifuged at 1000rpm for 5min and resuspended in PBS. Take 5X 104～1×105And (3) centrifuging the resuspended cells for 5min, removing the supernatant, collecting the cells, adding 195 mu L of Annexin V-FITC binding solution to lightly resuspend the cells, adding 5 mu L of Annexin V-FITC, lightly mixing, and incubating for 10min at room temperature (20-25 ℃) in the dark.
(3) Take 5X 104～1×105Resuspend the cells, centrifuge for 5min, discard the supernatant, add 190. mu.L Annexin V-FITC conjugate to resuspend the cells. Add 10. mu.L of propidium iodide staining solution, mix gently, place in ice bath and in dark.
(4) And (5) carrying out flow cytometry detection.
As shown in FIGS. 11 and 12, the apoptosis of CaSki and C33A cells of cervical cancer gradually increased with the increase of the isoliensinine treatment concentration.
According to the experimental results, the mechanism that isoliensinine is targeted to inhibit AKT from activating anti-cervical cancer proliferation, migration and apoptosis induction is shown in fig. 13, isoliensinine is activated by targeted inhibition pAKT (Ser 473 phosphorylation), expression of p21 is up-regulated, expression of Cyclin E1 and Cyclin-dependent kinase CDK2 is down-regulated, the cell cycle of cervical cancer is blocked at the G1 stage, and finally proliferation and migration of cervical cancer cells are inhibited and apoptosis is induced.
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (1)
1. The application of the isoliensinine in the preparation of the medicine for inhibiting the migration of the cervical cancer cells is characterized in that: the inhibition of cervical cancer cell migration is realized by targeting inhibition of AKT activation.
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| US20160106729A1 (en) * | 2014-01-03 | 2016-04-21 | Macau University Of Science And Technology | Group of Alkaloids, the Novel Autophagic Enhancers for Treatment of Cancers and Neurodegenerative Conditions Thereof |
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| US20160106729A1 (en) * | 2014-01-03 | 2016-04-21 | Macau University Of Science And Technology | Group of Alkaloids, the Novel Autophagic Enhancers for Treatment of Cancers and Neurodegenerative Conditions Thereof |
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| Betty Yuen Kwan Law等.Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells.《SCIENTIFIC REPORTS》.2014,第4卷(第5510期),第1-14页. * |
| Yi Yan等.Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5.《NATURE COMMUNICATIONS》.2015,第6卷(第6137期),第1-14页. * |
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