CN109908159B - Application of zoledronic acid and organic selenium compound in preparation of antitumor drugs - Google Patents
Application of zoledronic acid and organic selenium compound in preparation of antitumor drugs Download PDFInfo
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Abstract
The invention discloses an application of zoledronic acid and an organic selenium compound in preparation of an anti-tumor drug. In vitro cell experiments, the invention finds that the inhibition effect of the single organic selenium compound and the single zoledronic acid on the tumor cells is obviously inferior to that of combined medicines, and the combination of the organic selenium compound and the zoledronic acid can form a synergistic effect, namely, the aim of efficiently inducing the tumor cells to die can be achieved by utilizing the synergistic effect of the organic selenium compound and the zoledronic acid. In the invention, the potential action mechanism of the zoledronic acid for enhancing the growth of the organic selenium compound for inhibiting the growth of the prostate cancer cells is also found to be caused by inducing the cells to generate excessive ROS. Therefore, the zoledronic acid and the organic selenium compound can be combined to prepare an anti-tumor drug, or the zoledronic acid is used as a sensitizer of the organic selenium compound and is used in the field of tumor treatment.
Description
Technical Field
The invention relates to the technical field of tumor treatment, in particular to application of zoledronic acid and an organic selenium compound in preparation of antitumor drugs.
Background
Prostate cancer is one of the common malignancies of the male genitourinary system, and the incidence rate is on the rise year by year and tends to be younger, and because prostate cancer is hidden, its symptoms are often overlooked, and when diagnosed, about 65% to 75% of existing bone metastases. The prostate cancer bone metastasis can cause a series of bone related diseases, including pathological fracture, spinal cord compression, malignant tumor hypercalcemia and the like, and bone pain is the most common symptom of advanced prostate cancer, and seriously affects the life quality of patients. Therefore, how to relieve the pain of the patient and ensure the life quality of the patient while improving the treatment effect becomes a difficult problem which needs to be solved urgently in clinical treatment of the prostate cancer.
Zoledronic acid (ZOL), as a third generation of N-group-containing diphosphate drug, has been approved to be marketed in the United states and Europe since 2002, and has been proved by a plurality of clinical tests to have wide clinical curative effects on a plurality of primary malignant tumors, also show good curative effects in relieving bone metastasis pain of malignant tumors, and provide a new strategy for treating the bone metastasis pain of prostate cancer. Recent studies have further found that ZOL also has a direct tumor cell growth inhibiting effect. The current consensus view is that it inhibits tumor cell growth mainly by inhibiting the mevalonate pathway, affecting cellular protein prenylation, and damaging the membrane potential of cancer cells. This effect has been demonstrated in vitro assays of cancer cells such as breast cancer, osteosarcoma, and a prostate cancer.
Research results show that the selenadiazole derivative can inhibit the activity of TrxR in tumor cells, influence the removal of ROS, and enable the ROS to be rapidly accumulated in the tumor cells, so that DNA damage and cell cycle retardation are caused, and finally tumor cell apoptosis is induced. At present, the tumor chemotherapy is changed from the initial single medication to the combined medication, and plays a role in the aspects of mechanism complementation, effect synergy, adverse reaction reduction and the like. Chemotherapy sensitization belongs to a typical synergistic action mode in combined medication, and the sensitivity of tumor cells to chemotherapeutic drugs is improved by using a lower-dose sensitizer, and the tumor cells are killed together with the chemotherapeutic drugs. The method not only can obviously improve the chemotherapy efficiency, but also can effectively reduce the toxic and side effect of the chemotherapy drugs on normal cells, thereby successfully reversing the chemotherapy drug resistance. The advantages are mainly shown as follows: the single medicine can achieve a better synergistic effect by using a smaller dose, and overcomes the drug tolerance and serious toxic and side effects caused by single medicine with a larger dose. Secondly, drugs acting on different signal paths and different targets are combined for use, so that the signal paths can be comprehensively activated in all directions, and the anti-tumor effect is greatly enhanced. Therefore, the mode of the combined application of the novel organic selenium compound and a plurality of medicines is searched, and the synergistic effect among medicines is significant.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides the application of the zoledronic acid and the organic selenium compound in preparation of the antitumor drug.
The invention also aims to provide an anti-tumor combined medicament.
The purpose of the invention is realized by the following technical scheme: the combined application of zoledronic acid and organic selenium compounds in preparing antitumor drugs; the organic selenium compound is at least one of selenadiazole derivative and selenocysteine.
The selenadiazole derivative is preferably selected from
The anti-tumor medicament achieves the aim of treating tumors by inhibiting the growth and proliferation of the tumors and inducing the apoptosis of tumor cells.
The effective concentration of the zoledronic acid is 5-40 mu M; the effective concentration of the organic selenium compound is 0.25-8 mu M.
The tumor is prostatic cancer.
An anti-tumor composition comprises zoledronic acid and an organic selenium compound; the organic selenium compound is at least one of selenadiazole derivative and selenocysteine.
The selenadiazole derivative is preferably selected from
The tumor is prostatic cancer.
The effective concentration of the zoledronic acid is 5-40 mu M; the effective concentration of the organic selenium compound is 0.25-8 mu M.
The anti-tumor drug or the anti-tumor combined drug can also contain one or at least two pharmaceutically acceptable carriers.
The carrier is at least one of a sustained release agent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption enhancer, a surfactant and a lubricant.
The medicine can be prepared into various dosage forms by adopting a conventional method in the field, including powder, tablets, capsules, injection, powder injection, granules, oral liquid, syrup and the like.
The application of zoledronic acid in preparing sensitizer of organic selenium compound; the organic selenium compound is at least one of selenadiazole derivative and selenocysteine.
The selenadiazole derivative is preferably selected from
The effective concentration of the zoledronic acid is 5-40 mu M.
Compared with the prior art, the invention has the following advantages and effects:
1. the research of the invention finds that zoledronic acid (ZOL) has certain effect of inhibiting the growth and proliferation of tumor cells, organic selenium compounds (SeC and SeD) can induce the apoptosis of the tumor cells, the inhibition effect of the single organic selenium and the single ZOL on PC-3 tumor cells is obviously different from that of combined drugs, the ZOL and the organic selenium form a synergistic effect, the organic selenium compounds have high-efficiency inhibition effect on prostate cancer cells PC-3 in vitro cell experiments, and the result indicates that the ZOL can enhance the killing of tumors by the organic selenium compounds, so the synergistic action mode of the ZOL and the organic selenium compounds can be used as a novel anti-tumor strategy, namely, the synergistic effect of the organic selenium compounds and the zoledronic acid is utilized to achieve the purpose of efficiently inducing the apoptosis of the tumor cells.
2. The invention also finds that ZOL alone acts on PC-3 cells to cause the decrease of intracellular ROS, while SeD and SeC alone cause the tumor cells to generate a large amount of ROS accumulated in the cells, and when ZOL is combined, the ROS is excessively accumulated in the tumor cells. Therefore, the potential mechanism of action of ZOL to enhance the growth of organoselenium compounds in inhibiting prostate cancer cells is caused by the induction of excess ROS produced by the cells.
Drawings
FIG. 1 is a graph showing the effect of ZOL in combination with SeC on the survival rate of PC-3 cells (ZOL in combination with SeC treatment time 72 h; density of PC-3 cells 20000 cells/mL).
FIG. 2 is a photograph of cells treated with ZOL in combination with SeC for 72 hours.
FIG. 3 is a graph showing ROS production by cells after ZOL combined with SeC treatment.
FIG. 4 is a graph showing the effect of ZOL in combination with SeD on the survival rate of PC-3 cells (the treatment time of ZOL in combination with SeD was 72 hours; the density of PC-3 cells was 20000 cells/mL).
FIG. 5 is a photograph of cells treated with ZOL in combination with SeD for 72 hours.
FIG. 6 is a graph showing ROS production by cells after ZOL combined with SeD treatment.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. Unless otherwise specified, the agents and medicaments used in the present invention are commercially available.
The structural formula of the selenadiazole derivative (SeD) referred to in the examples is:
selenocysteine (SeC) referred to in the examples has the formula: C3H7NO2 Se.
Zoledronic acid (ZOL) referred to in the examples is a clinical drug and is commercially available from a conventional commercial source.
Example 1 in vitro anti-prostate tumor Activity study of ZOL in combination with organic selenium Compounds
In this experiment, the in vitro anti-tumor activity of the organic selenium compound and ZOL combination on prostate cancer PC-3 cells was studied. We expect to develop new strategies for the treatment of tumors with synergistic chemotherapy.
(1) Prostate cancer cells (PC-3 cells; purchased from American model culture Collection) were taken at a density of 2X 10 in logarithmic growth phase4cells/mL were seeded in 96-well plates (100. mu.L/well) and allowed to grow adherently for 2 hours. PC-3 cells were pretreated with 20. mu.M ZOL for 8h, followed by addition of 2. mu.M SeC and SeD (100. mu.L) of organoselenium compounds, respectively, to 96-well plates, incubation continued for 64 h with no ZOL and organoselenium compounds added as blanks, and after the time had elapsed, 25. mu.L of MTT solution (5mg/mL, PBS buffer) was added to each well and incubated for 4 h. The supernatant culture solution in the 96-well plate was removed, 150. mu.L of DMSO (dimethyl sulfoxide) solution was added, and the mixture was placed on a shaker and gently shaken for 15 minutes to dissolve the purple crystals in the 96-well plate sufficiently. Then, measuring the light absorption value (OD570) of each hole under 570nm by using a multifunctional microplate reader, and calculating the cell survival rate; wherein the cell survival (%) is ═ (OD570 experimental/OD 570 control) x 100%. The results are shown in FIGS. 1, 2, 4 and 5.
As can be seen from FIG. 1, PC-3 cells treated with ZOL alone had little effect on cell survival and had a general effect of inhibiting tumor cell proliferation; when the cells were treated with the organoselenium compounds SeC and SeD (FIGS. 1 and 4), the survival rate of PC-3 cells was found to decrease by 50% and 30%, respectively. In the treatment group combining ZOL (ZOL plays a sensitization role in the range of 5-40 mu M, and the ZOL concentration used in the experiment is 20 mu M) and organic selenium, the survival rate of PC-3 cells is reduced to 37% and 20% respectively.
(2) After the drugs act on the PC-3 cells, under the condition that the survival rate of the PC-3 cells is the same, the drug concentrations of the three schemes of treating with ZOL alone and treating with organic selenium alone and acting with the PC-3 cells in combination are calculated respectively, so that the method for treating the tumors by the combination of ZOL and the organic selenium compounds is proved to have better tumor treatment effect and reduce the needed drug amount. The specific experimental process is as follows:
1) PC-3 cells were treated with 20 μ M ZOL alone, and cell viability was calculated after 72 hours in triplicate, and the results are shown in table 1.
TABLE 1 cell viability after ZOL alone (20 μ M) treatment for 72 hours
| Average absorbance of control group | 0.465 |
| Average absorbance of individual ZOL groups | 0.287 |
| Survival rate | 0.2877/0.465*100＝61％ |
2) The organic selenium compound (SeC; SeD) treating the PC-3 cells, and calculating the cell survival rate after 72 hours; PC-3 cells were pretreated with 20. mu.M ZOL for 8h, then 1, 2, 4, 8. mu.M organoselenium compound (SeC; SeD) was added thereto, and incubation was continued for 64 hours, and the cell viability was calculated, the results of which are shown in Table 2.
TABLE 2 cell survival rates of organoselenium compounds alone and in combination for 72 hours
According to the data in table 2, a fitting graph formula of the drug concentration and the survival rate in the cell survival rate experiment is obtained:
fit curve of survival rate and concentration of individual SeD action: y-0.0264 x +2.7051, R2＝1，
Fitting a curve of survival rate and concentration of SeC action alone: 608.95x-1.471，R2＝0.9804；
③ survival rate of SeD in ZOL (20. mu.M) in combination with SeD fitted curve with concentration: 807.9x-1.643，R2＝0.9827；
Survival rate of SeC in combination with SeC by ZOL (20 μ M) was fitted to the concentration curve: 1919.3x-1.866，R2＝0.9984；
In the formula: x is survival rate and y is drug concentration.
Then, according to the above formula, the corresponding drug concentration when the cell survival rate is 61% (obtained by converting the survival rate of 61% into the corresponding formula) is calculated:
PC-3 cells were treated with ZOL alone (20 μ M) to achieve 61% cell viability, while the concentration of SeD alone required to achieve 61% cell viability was 1.09 μ M, whereas in the ZOL in combination with SeD experimental group, 20 μ M ZOL and 0.94 μ M SeD resulted in a similar 61% cell viability reduction; similarly, the concentration of SeC alone required to achieve 61% cell viability was 1.44 μ M, whereas in the ZOL in combination with SeC experimental group, 20 μ M ZOL and 0.89 μ M SeC were able to achieve the same 61% cell viability. The combined treatment of the two medicines reduces the concentration of the medicine, and is beneficial to reducing the toxic and side effects of the medicine on normal cells. Cell inhibition was shown when treated with organoselenium and ZOL, respectively; and when ZOL and organic selenium act together, the treatment group shows more obvious inhibition effect. This conclusion can also be drawn from the cell photographs of fig. 2 and 5.
Example 2 study of the Effect of ZOL on ROS levels in prostate tumors by Co-action with organoselenium Compounds
Excessive accumulation of reactive oxygen species ROS in cells is an important initial signal for causing cell damage, so we examined the effect of ZOL in combination with organic selenium compounds (SeC, SeD) on cellular ROS production after acting on prostate cancer cells by DHE probe staining. The specific method comprises the following steps:
inoculating cells into a 96-well plate according to the density of 20 ten thousand cells/mL, after the cells are attached to the wall for 24 hours (the culture medium used for culturing the cells is a DMEM culture medium), respectively adding 50 mu L of 20 mu M ZOL to incubate for 2-8 hours according to requirements, then replacing the DMEM culture medium with 20 mu M DHE probes in each hole and 100 mu L DHE probes, culturing for 30min in a dark place, respectively adding SeC and SeD (the concentration of SeC and SeD can be 0.25-8 mu M; the concentration of SeC and SeD adopted in the embodiment is 4 mu M) after ZOL incubation is finished according to the requirements of each group, and immediately detecting the fluorescence intensity in the holes by a fluorescence microplate reader with the excitation wavelength and the emission wavelength respectively set to be 310nm and 600nm after the probe incubation is finished.
The results are shown in FIGS. 3 and 6: ZOL alone, when applied to PC-3 cells, causes a decrease in intracellular ROS. Whereas SeD and SeC alone cause tumor cells to produce large amounts of ROS, especially SeC alone. Although the patterns and amounts of ROS produced by PC-3 cells of prostate cancer induced by these two organoselenium compounds are different, when combined with ZOL, both result in excess ROS accumulation in tumor cells. Therefore, the potential mechanism of action of ZOL to enhance the growth of organoselenium compounds in inhibiting prostate cancer cells is caused by the induction of excess ROS produced by the cells.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (2)
1. The application of the combination of zoledronic acid and organic selenium compound in preparing antitumor drugs is characterized in that:
the organic selenium compound is selenocysteine;
the tumor is prostate cancer;
the effective concentration of the zoledronic acid is 20 mu M, and the effective concentration of the organic selenium compound is 1-4 mu M.
2. The use of zoledronic acid in combination with an organic selenium compound as claimed in claim 1, for the preparation of an antitumor medicament, wherein:
the anti-tumor medicament achieves the aim of treating tumors by inhibiting the growth and proliferation of the tumors and inducing the apoptosis of tumor cells.
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