CN106466305A - Metformin is used for purposes and pharmaceutical composition in preparation treatment and/or prevention head and neck scale carcinoma medicine - Google Patents
Metformin is used for purposes and pharmaceutical composition in preparation treatment and/or prevention head and neck scale carcinoma medicine Download PDFInfo
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- CN106466305A CN106466305A CN201610738212.9A CN201610738212A CN106466305A CN 106466305 A CN106466305 A CN 106466305A CN 201610738212 A CN201610738212 A CN 201610738212A CN 106466305 A CN106466305 A CN 106466305A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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Abstract
The invention belongs to biomedicine field, it is used for the purposes in preparation treatment and/or prevention head and neck scale carcinoma medicine and pharmaceutical composition in particular to metformin.For solve prior art present in technical problem, provide a kind of metformin for preparation treatment and/or prevent head and neck scale carcinoma medicine in purposes.The metformin of the present invention can effectively induce the anoikis of head and neck scale carcinoma FaDu cell in glucose starvation environment；Thus metformin can be used for preparing the medicine for the treatment of head and neck scale carcinoma；Build the environment of glucose starvation by low sugar meals, be conducive to metformin to suppress the growth of head and neck scale carcinoma；The present invention also provides a kind of pharmaceutical composition, including as the metformin of active component and one or more pharmaceutically acceptable adjuvant or excipient.Effective extension metformin is treated in glucose starvation environment the purposes of head and neck scale carcinoma, the effective control to head and neck scale carcinoma and prevention be can achieve by being used in combination of multiple dosage forms.
Description
Technical field
The invention belongs to biomedicine field, it is used for preparation treatment and/or prevention head in particular to by metformin
Purposes in carcinoma of neck medicine and pharmaceutical composition.
Background technology
Head and neck scale carcinoma is one of common malignant tumor in the world.Head and neck scale carcinoma includes throat scale cancer, oral squamous cell carcinomas etc..At present
Treatment for head and neck scale carcinoma mainly adopts excision, chemotherapy and radiotherapy.Medicine is less at present, and existing treatment plan
Slightly only has the 3-4 month for recurrent transfer its median survival interval of patient.Metformin is mainly used in the treatment of type-II diabetes.?
Near clinical research shows that metformin can significantly reduce the cancered risk of type-II diabetes patient.But its molecular mechanism is also
Unclear.Conventional chemotherapeutics have cisplatin, 5-fluorouracil and paclitaxel.Additionally, current therapeutic strategy is for relapse and metastasis
Its median survival interval of head and neck cancer patient be only the 3-4 month, fully show the grade malignancy of this disease and explore new therapeutic strategy
Necessity.
Content of the invention
It is an object of the invention to solving technical problem present in above prior art, a kind of metformin is provided to be used for
Purposes in preparation treatment and/or prevention head and neck scale carcinoma medicine and pharmaceutical composition.It is in the environment of glucose starvation in cell
Under, the anoikis of head and neck scale carcinoma FaDu cell can be significantly induced using metformin.
An object of the present invention is achieved through the following technical solutions：
Metformin is used for the purposes in preparation treatment and/or prevention head and neck scale carcinoma medicine.
Further, described head and neck scale carcinoma is in glucose starvation environment.
Further, described glucose starvation environment is the blood sugar concentration of cell local environment less than 2.5mg/mL.
Further, described glucose starvation environment is containing 1,5-anhydroglucitol（2-DG）Blood glucose environment.
Another object of the present invention is achieved through the following technical solutions：
A kind of pharmaceutical composition, including as the metformin of active component and one or more pharmaceutically acceptable adjuvant
Or excipient.
Further improvement be, including as the metformin of active component, hypoglycemic drug active component, a kind of or many
Plant pharmaceutically acceptable adjuvant or excipient.
Further improvement be, including as the metformin of active component, 1,5-anhydroglucitol and one or more
Pharmaceutically acceptable adjuvant or excipient.
Further improvement is that the dosage form of this pharmaceutical composition is tablet, dragee, granule, gelatine capsule, injectable
Preparation, drinkable suspensoid or disintegratable paste.
The present invention with respect to the beneficial effect of prior art is：The metformin of present invention energy in glucose starvation environment
Effectively induce the anoikis of head and neck scale carcinoma FaDu cell；Thus, metformin can be used as the new clinical treatment medicine of head and neck scale carcinoma
Thing；Build the environment of glucose starvation by low sugar meals, be conducive to metformin to suppress the growth of head and neck scale carcinoma；And normal
Or be higher than in normal blood sugar concentration environment, it will be a kind of new head and neck scale carcinoma treatment plan that metformin and 2-DG are used in combination
Slightly.Metformin according to the present invention is used in preparation treatment and/or prevention head and neck scale carcinoma medicine in glucose starvation environment
Purposes make medicine for treating head and neck scale carcinoma, will effectively extend metformin and treat head and neck in glucose starvation environment
The mode of scale cancer, can achieve the effective control to head and neck scale carcinoma and prevention by being used in combination of multiple dosage forms.
Brief description
The anoikis schematic diagram of Fig. 1 head and neck scale carcinoma cell.
The impact to head and neck scale carcinoma FaDu cell attachment cell number for the metformin under Fig. 2 difference concentration of glucose is illustrated
Figure.
, under the conditions of LG, different process times is to head and neck scale carcinoma FaDu cells survival rate for Fig. 3 metformin
Impact schematic diagram.
The head and neck scale carcinoma FaDu cell mistake nest that Fig. 4 metformin processes 0 hour and 36 hours under low glucose concentrations withers
Situation of dying contrast schematic diagram.
Fig. 5 metformin under high glucose concentration is pasted to head and neck scale carcinoma FaDu cell from the different service conditions of 2-DG
The impact schematic diagram of parietal cell number.
Fig. 6 metformin under high glucose concentration is given birth to head and neck scale carcinoma FaDu cell from the different service conditions of 2-DG
Deposit the impact schematic diagram of rate.
The different service conditions of Fig. 7 metformin and 2-DG under high glucose concentration are to apoptosis mark PARP1
Impact schematic diagram.
The apoptosis of Fig. 8 metformin and different service conditions of 2-DG under high glucose concentration（AnnexinV/PI
Double dyes）Situation schematic diagram.
Fig. 9 is used in combination head and neck squama gross tumor volume in the nude mice body under metformin and 2-DG different time in nude mouse
Comparison schematic diagram.
The different service conditions of Figure 10 metformin and 2-DG in nude mice body under same time are to head and neck squama tumor weight
The impact schematic diagram of amount.
Figure 11 metformin under different concentration of glucose affects schematic diagram to p63 albumen.
Figure 12 metformin under high glucose concentration affects schematic diagram from the different service conditions of 2-DG to p63 albumen.
Figure 13：In Figure 10, the different service conditions of metformin and 2-DG are to the p63 albumen in head and neck squama tumor tissues
Expression impact schematic diagram；
Figure 14 under low glucose concentrations, paste to head and neck scale carcinoma FaDu cell by the different service conditions of p63 albumen and metformin
The impact schematic diagram of parietal cell number.
Wherein, in accompanying drawing（+）Represent and use,（-）Represent and do not use, Con represents blank, Met represents that diformazan is double
Guanidine, 2-DG represents 1,5-anhydroglucitol.
Specific embodiment
Below in conjunction with drawings and Examples, the metformin of the present invention is used for preparation treatment and/or prevention head and neck scale carcinoma medicine
The technical scheme of the purposes in thing and pharmaceutical composition is described in detail, so that those skilled in the art is reading this
Can be sufficiently complete on the basis of invention book realize technical scheme, and solve existing skill to be solved by this invention
Problem present in art.It should be noted that following is only the preferred embodiment of the present invention, for the ordinary skill of this area
For personnel, without departing from the concept of the premise of the invention, some deformation can also be made and improve, these should all belong to
In protection scope of the present invention.
Certain medicine addition X mmol/L in the present invention refers to add this medicine of X mmol in every liter of blood in human body
Thing.
Heretofore described glucose starvation environment, refers at least one in following state：
1st, blood glucose（Glucose）Concentration is less than the blood glucose environment of 2.5 mg/mL；
2nd, contain 1,5-anhydroglucitol（2-DG）Blood glucose environment.
Embodiment 1
First, hypoglycemia environment promotes metformin to induce the anoikis of head and neck scale carcinoma FaDu cell.
In Fig. 1-Fig. 4, the consumption of metformin is 20 mmol/L.
The anoikis process of head and neck scale carcinoma FaDu cell as shown in figure 1, attached cell is after departing from its growth position,
And then generation apoptosis.
Fig. 2 is to be separately added into 20 mmol/ under the conditions of blood sugar concentration is 4.5 mg/mL and blood sugar concentration is 1.0 mg/mL
The metformin of L processes FaDu cell 24 hours, calculates attached cell number by blood counting chamber and draws.As Fig. 2 institute
Show, when blood sugar concentration is 4.5 mg/mL, metformin does not produce impact to head and neck scale carcinoma FaDu cell, in blood sugar concentration
During for 1.0 mg/mL, the attached cell number of head and neck scale carcinoma FaDu cell significantly reduces, and illustrates that diformazan is double in hypoglycemic environment
Guanidine has a significant effect to the existence of suppression head and neck scale carcinoma FaDu cell；As shown in figure 3, in hypoglycemic environment, with
The growth of the process time of metformin, the survival rate of head and neck scale carcinoma FaDu cell substantially reduces, as shown in Figure 4, double in diformazan
Guanidine processes 36 hours afterwards to head and neck scale carcinoma FaDu cell, and the head and neck scale carcinoma FaDu cell close to 90% occurs anoikis, shows
Blood glucose starvation can promote metformin to induce the anoikis of head and neck scale carcinoma cell, it should be noted that less than 2.5mg/
Carrying out above-mentioned experiment under mL blood sugar concentration all can promote metformin to induce the anoikis of head and neck scale carcinoma cell.In sum
Understand, blood glucose starvation can significantly strengthen the viability that metformin suppresses head and neck scale carcinoma FaDu cell.
2nd, metformin and 2-DG are used in combination the significant anoikis inducing head and neck scale carcinoma FaDu cell.
As shown in Figure 5-Figure 8.In Fig. 5-Fig. 8, the addition of metformin is 20 mmol/L, 1,5-anhydroglucitol (2-
DG addition) is 20 mmol/L, and the process time to head and neck scale carcinoma FaDu cell is 24 hours.1,5-anhydroglucitol（2-
DG）It is a glycolytic inhibitor, it can suppress the absorption to glucose for the cell, thus analog cell is in glucose
Hungry environment.As shown in figure 5, in high blood glucose concentration（Concentration of glucose is 4.5 mg/mL）In the case of simultaneously using 2-DG and
Metformin can significantly cause the de- wall of head and neck scale carcinoma FaDu cell；As shown in fig. 6, in high blood glucose concentration（Glucose is dense
Spend for 4.5 mg/mL）In the case of, 2-DG is used in combination and metformin significantly suppresses the existence of head and neck scale carcinoma FaDu cell
Power.As shown in fig. 7, in high blood glucose concentration（Concentration of glucose is 4.5 mg/mL）In the case of, 2-DG and metformin are used in combination
The shearing of apoptosis mark PARP1 can be dramatically increased.Under high blood glucose concentration as shown in Figure 8, metformin and 2-DG be not
Head and neck scale carcinoma FaDu apoptosis with service condition show：In high blood glucose concentration（Concentration of glucose is 4.5 mg/mL）Situation
Under, 2-DG is used in combination and metformin significantly induces the anoikis of head and neck scale carcinoma FaDu cell.To sum up show, combine and make
The anoikis of head and neck scale carcinoma FaDu cell can significantly be induced with metformin and glycolytic inhibitor 2-DG, thus suppressing
Its existence.
3rd, metformin and 2-DG are used in combination the significant one-tenth knurl ability suppressing head and neck scale carcinoma cell in animal model.
As shown in Figure 9 and Figure 10.Fig. 9 and Figure 10 is drawn by following experiments：In every female BAl BIc/C nude mice（Five
Week old, every group 8）Right cervical region injects 2*106Individual head and neck scale carcinoma FaDu cell, when the 16th day, nude mice abdominal cavity individually or
Combine injection 400 mg/kg metformin and 400 mg/kg 2-DG（Every kg nude mice body weight adds 400mg）, matched group injection etc.
The normal saline of amount, injection in every two days is once.Measure gross tumor volume from injecting cell the 16th day within every 4 days（Gross tumor volume=[（Long
Degree * width2）/2]）, obtain Fig. 9, took out tumor when the 32nd day and weigh tumor weight, obtain Figure 10.As shown in figure 9, with
The prolongation of time, is used in combination metformin and 2-DG can significantly suppress the growth of gross tumor volume in nude mice body；As Figure 10 institute
Show, when the 32nd day, minimum with the tumor weight of the nude mice of the therapeutic alliance of 2-DG through metformin.To sum up, it is used in combination
Metformin and 2-DG can also significantly suppress one-tenth knurl ability in nude mice body for the FaDu cell.
4th, p63 is in joint metformin and glucose starvation environment（Low sugar, 2-DG）Suppression head and neck scale carcinoma growth course
In play an important role.
As illustrated in figs. 11-14.Figure 11 is under low levels（Concentration of glucose is 1.0 mg/mL）, use 10 mmol/L
Metformin processes FaDu cell 24 hours, draws through the protein expression of immune-blotting method p63.Figure 12 is double in diformazan
Guanidine and 2-DG joint or individual processing FaDu cell 24 hours, draw through the protein expression of immune-blotting method p63.Figure
In 32nd day tumor tissues in 13 immunohistochemical analysis Figure 10, the expression of p63 draws.Figure 14 is in low sugar concn（Fructus Vitis viniferae
Sugared concentration is 1.0 mg/mL）Under, the FaDu cell of metformin process overexpression p63 24 hours, proceed to the FaDu cell of zero load
As comparison, observation of cell takes off wall phenomenon, and blood counting chamber counts what attached cell number drew.P63 is Suppressor p53
Family protein, p63 plays an important role in regulating cell adhesion process.Inventor research find, low glucose concentrations and
2-DG can significantly promote metformin to reduce the expression of p63.As shown in figure 11, in hypoglycemia（Concentration of glucose is 1.0
mg/mL）Under concentration, metformin significantly decreases the expression of p63；As shown in figure 12, in hyperglycemia（Concentration of glucose is 4.5
mg/mL）Under concentration, add 2-DG can be obviously promoted the expression that metformin reduces p63；As shown in figure 13, it is being used in combination
Metformin and 2-DG can effectively reduce the expression of p63 in tumor tissues；As shown in figure 14, under low levels（Fructus Vitis viniferae
Sugared concentration is 1.0 mg/mL）Add the FaDu cell that metformin processes overexpression p63 can effectively recover metformin and cause head
The de- wall phenomenon of carcinoma of neck FaDu cell.Show that p63 limits in joint metformin and glucose（Low sugar, 2-DG）Suppression head and neck
Play an important role in scale cancer growth course.In sum, by can be effective using metformin in glucose starvation environment
Prevention and treatment head and neck scale carcinoma, effectively suppresses the growth of head and neck scale carcinoma cell, and the cell that p63 induces in metformin simultaneously loses nest
Play an important role in apoptosis.
Embodiment 2
Metformin based on the present invention is used for the purposes in preparation treatment and/or prevention head and neck scale carcinoma medicine, and the present invention also carries
For a kind of pharmaceutical composition, including as the metformin of active component, hypoglycemic drug active component, one or more pharmacy
Upper acceptable adjuvant or excipient.
The active component of described hypoglycemic drug includes insulin and the like, sulfonylurea acyl class promotees to secrete agent, metformin
Class, alpha-glucosidase inhibitor, tetrahydrothiazole diketone derivatives promote quick dose, benzene fennel acid derivative promote secrete agent, GLP-1 receptor
Any one or a few in active component in agonist, DDP-4 enzyme inhibitor and Chinese patent medicine etc..By hypoglycemic drug
Active component builds glucose starvation environment, thus realizing the therapeutic effect of metformin.Diformazan is selected according to conventional consumption
Biguanide and hypoglycemic drug active component, make medicine using conventional technique and pharmaceutically acceptable adjuvant or excipient
Compositionss.
Preferably, this pharmaceutical composition include metformin as active component, 1,5-anhydroglucitol and a kind of or
Multiple pharmaceutically acceptable adjuvants or excipient.By metformin and 1,5-anhydroglucitol are made doctor as active component
Receivable dosage form on, thus realize in effect that is normal or being higher than treatment head and neck scale carcinoma in normal blood glucose environment.According to
Conventional consumption selects metformin and 1,5-anhydroglucitol, using conventional technique and pharmaceutically acceptable adjuvant or figuration
Agent and make pharmaceutical composition.
Specifically, can also by conventional technique means select to include using metformin and hypoglycemic drug as
Active component or using metformin and 1,5-anhydroglucitol as the following dosage form that active component is made include tablet, dragee,
Granule, gelatine capsule, injectable formulation, drinkable suspensoid or disintegratable paste.
Technical scheme can be fully realized in record according to this specification.
Claims (8)
1. metformin is used for the purposes in preparation treatment and/or prevention head and neck scale carcinoma medicine.
2. purposes according to claim 1 is it is characterised in that described head and neck scale carcinoma is in glucose starvation environment.
3. purposes according to claim 2 is it is characterised in that described glucose starvation environment is the blood of cell local environment
Sugared concentration is less than 2.5mg/mL.
4. purposes according to claim 2 is it is characterised in that described glucose starvation environment is containing 1,5-anhydroglucitol
（2-DG）Blood glucose environment.
5. a kind of pharmaceutical composition is it is characterised in that include the metformin as active component and one or more pharmacy
Upper acceptable adjuvant or excipient.
6. pharmaceutical composition according to claim 5 is it is characterised in that include the metformin as active component, fall
Hypoglycemic medicament active component, one or more pharmaceutically acceptable adjuvant or excipient.
7. pharmaceutical composition according to claim 5 is it is characterised in that include the metformin as active component, 2-
Deoxyglucose and one or more pharmaceutically acceptable adjuvant or excipient.
8. the pharmaceutical composition according to claim 5-7 any one is it is characterised in that the dosage form of this pharmaceutical composition is
Tablet, dragee, granule, gelatine capsule, injectable formulation, drinkable suspensoid or disintegratable paste.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610738212.9A CN106466305A (en) | 2016-08-26 | 2016-08-26 | Metformin is used for purposes and pharmaceutical composition in preparation treatment and/or prevention head and neck scale carcinoma medicine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610738212.9A CN106466305A (en) | 2016-08-26 | 2016-08-26 | Metformin is used for purposes and pharmaceutical composition in preparation treatment and/or prevention head and neck scale carcinoma medicine |
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| CN201610738212.9A Pending CN106466305A (en) | 2016-08-26 | 2016-08-26 | Metformin is used for purposes and pharmaceutical composition in preparation treatment and/or prevention head and neck scale carcinoma medicine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013019058A2 (en) * | 2011-08-04 | 2013-02-07 | Hanall Biopharma Co., Ltd. | Pharmaceutical composition for inhibiting cancer recurrence or metastasis |
-
2016
- 2016-08-26 CN CN201610738212.9A patent/CN106466305A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013019058A2 (en) * | 2011-08-04 | 2013-02-07 | Hanall Biopharma Co., Ltd. | Pharmaceutical composition for inhibiting cancer recurrence or metastasis |
Non-Patent Citations (2)
| Title |
|---|
| ARRON SIKKA等: "Metformin suppresses growth of human head and neck squamous cell carcinoma via global inhibition of protein translation", 《CELL CYCLE》 * |
| VLAD C. SANDULACHE等: "Glucose, Not Glutamine, Is the Dominant Energy Source Required for Proliferation and Survival of Head and Neck Squamous Carcinoma Cells", 《CANCER》 * |
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Application publication date: 20170301 |