ES2398586T3 - Use of the CK2 inhibitor for the treatment and chemosensitization of tumors resistant to anticancer drugs - Google Patents

Abstract

The present invention relates to a pharmaceutical combination that includes a Casein Kinase 2 phosphorylation inhibitor (called P15) and the cytostatics used in cancer chemotherapy which are administered simultaneously, separately or sequentially. Preferred cytostatics are platinums, taxanes, Vinca alkaloids, 5-fluorouracil, doxorubicin, cyclophosphamide, etoposide, mitomycin C, imatinib, iressa, and velcade (vortezomib). The synergy between peptide P15 and anticancer chemical compounds means that the effective concentration of each cytostatic in the combination is between one and two orders of magnitude lower than that of the cytostatics alone. Consequently, the combination described in the invention has a much lower toxicity than that reported for anticancer cytostatics, which represents a crucial advantage for its use in cancer treatment. Additionally, the sequentially administered combination produces chemosensitization of tumors refractory to the aforementioned cytostatics by pretreatment with peptide P15.

Description

Use of the CK2 inhibitor for the treatment and chemosensitization of tumors resistant to anticancer drugs

Technical field

The present invention relates to the field of molecular and experimental oncology, in particular to the description of a pharmaceutical combination directed to the treatment and / or chemosensitization of conventional cytostatic refractory tumors.

Prior art

In the last three decades, the use of chemical drugs as cytostatics for cancer therapy constitutes one of the choices as a first-line treatment for some solid and hematopoietic tumors. The most commonly used chemical drugs for cancer therapy are: Cisplatin, taxols, vinca alkaloids, doxorubicin, 5-fluorouracil, cyclophosphamide among others (Jackman AL, Kaye S., Workman P. (2004) The combination of cytotoxic and molecularly targeted therapies-can it be done? Drug Discovery Today 1: 445-454). However, the results of clinical trials exhibit a low therapeutic index for this type of drug in cancer therapy, as evidenced by the minimum therapeutic benefit together with the high toxicity profile observed in patients (Schrader C. , et al., M. (2005) Symptoms and signs of an acute myocardial ischemia caused by chemotherapy with paclitaxel (taxol) in a patient with metastatic ovarian carcinoma. Eur J Med Res 10: 498-501). For example, many authors agree that cisplatin is the first-line treatment for lung cancer, however, modest efficacy is usually observed with little improvement in clinical symptoms and a 6-week increase in survival (Cricket R., Oxman A., Julian J. (1993) Chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 11: 1866-1871; Bouquet PJ, Chauvin F., et al (1993) Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 342: 19-21). Therefore, current strategies to achieve optimal therapeutic benefit focus on pharmaceutical combinations based on conventional cytostatic drugs along with targeted molecular therapies. Some of the current anticancer drugs are classified as cancer-directed therapy, for example Gleevec (Imatinib) which is directed at Abl kinase which, in turn, plays an essential role in the development of chronic myeloid leukemia (Giles JF, Cortes JE, Kantarjlan HM (2005) Targeting the Kinase Activity of the BCR-ABL Fusion Protein in Patients with Chronic Myeloid Leukemia. Current Mol Med 5: 615-623), also Iressa whose objective is the tyrosine kinase associated with the factor receptor epidermal growth (EGF) (Onn A., Herbst RS (2005) Molecular targeted therapy for lung cancer. Lancet 366: 1507-1508) and Velcade (Bortezomib) that blocks protein degradation on proteasome machinery (Spano JP, et al. ., (2005) Proteasome inhibition: a new approach for the treatment of malignancies. Bull Cancer 92: E61-66), among others. Considering that the nonspecific mechanisms of conventional chemotherapeutics converge on the cancellation of cell mitosis, the use of new cancer-directed therapies provides great prospects for achieving pharmaceutical combinations that produce synergy of the antitumor effect.

On the other hand, the phenomenon of drug resistance has been recognized as the main cause of cancer therapy failure when chemotherapeutic agents are used. Although the suboptimal concentration of the drug on the tumor environment could influence drug resistance, other factors such as cellular origin play an essential role in chemoresistance for many tumors. Drug resistance is a multifactorial phenomenon that depends on multiple independent mechanisms that involve intracellular detoxification, changes in cell response, stress tolerance and defects in apoptosis signaling pathways (Luqmani A. (2005) Mechanisms of drug resistance in cancer chemotherapy, Med Princ. Pract 14: 35-48). P-glycoprotein and glutathione-S-transferase are the main proteins involved in the intracellular detoxification process linked to the phenomenon of drug resistance in cancer (Saeki T., Tsuruo T., Sato W., Nishikawsa K. (2005 ) Drug resistance in chemotherapy for breast cancer Cancer Chemother Pharmacol 56: 84-89) (Hara T., et al. (2004) Gluthathione S-transferase P1 has protective effects on cell viability against camptothecin. Cancer Letters 203: 199- 207). It has been reported that other proteins such as beta-tubulins are involved in the phenomenon of drug resistance and whose levels correlate directly with the tumor resistance to Paclitaxel (Orr GA, et al., (2003) Mechanisms of Taxol resistance related to microtubules Oncogene 22: 72807295). Otherwise, it has been reported that cisplatin resistance is affected by the overexpression of different proteins, such as T-plastine (Hisano T., et al., (1996) Increased expression of T-plastin gene in cisplatinresistant human cancer cells : identification by mRNA differential display, FEBS Letters 397: 101-107), heat shock protein (HSP70) and (HSP90) (Jaattela M. (1999) Escaping cell death: survival proteins in cancer. Exp Cell Res 248: 30 -43) and the transcription factor YB1 (Fujita T., et al., (2005) Increased nuclear localization of transcription factor Y-box binding protein accompanied by up-regulation of P-glycoprotein in breast cancer pretreated with paclitaxel. Clin Cancer Res 11: 8837-8844). Additionally, it has been reported that exacerbation of glycolysis and pyruvate pathways play an essential role in the chemoresistance phenomenon observed in tumor cells (Boros LG, et al., (2004) Use of metabolic pathway flux information in targeted cancer drug design. Drug Disc. Today 1: 435-443).

Reports from different groups have indicated the existence of a set of proteins that inhibit apoptosis or increase cell survival on tumor cells, so that they contribute to the phenomenon of chemoresistance of tumors. One example is the nucleophosmin protein, which plays a central role in cell cycle stimulation, apoptosis inhibition and has been considered a marker of poor prognosis in cancer (Ye K. (2005) Nucleophosmin / B23, a multifunctional protein that can regulate apoptosis Cancer Biol Ther 4: 918-923). Likewise, the enzyme CK2 plays an important role on cell survival and in the resistance of tumor cells to apoptosis (Tawfic S., Yu S., Wang H., Faust R., Davis A., Ahmed

K. (2001) Protein kinase CK2 signal in neoplasia. Histol Histopathol 16: 573-582). The above findings have revealed the elevation of CK2 activity 3 to 7 times and solid epithelial tumors with respect to normal tissues (Tawfic S., Yu S., et al., (2001) Protein kinase CK2 signal in neoplasia. Histol Histopatol 16: 573-582; Faust RA, Gapany M., et al. (1996) Elevated protein kinase CK2 activity in chromatin of head and neck tumors: association with malignant transformation. Cancer Letters 101: 31-35). In addition, CK2 activity is an important cellular event for malignant transformation and constitutes a marker of tumor progression (Seldin DC, Leder P. (1995) Casein Kinase IIα transgene induced murine lymphoma: relation to theileroiosis in cattle. Science 267: 894-897). The fact that CK2 phosphorylation represents a strong signal to protect tumor cells from apoptosis, leads to the consideration of this enzyme as an antiapoptotic mediator on cell physiology (Ahmed K., Gerber DA, Cochet C. (2002) Joining the cell survival squad: an emerging role for protein kinase CK2 Trends Cell Biol, 12: 226-229; Torres J., Rodriguez J., et al. (2003) Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase- 3: implications for the control of protein stability and PTENprotein interactions. J Biol Chem, 278: 30652-60).

Together, CK2 phosphorylation is a biochemical event that represents a possible target for cancer therapy and the specific inhibitors of this event could lead to drug candidates with perspectives for cancer treatment.

Different groups have developed different approaches to inhibit CK2 phosphorylation using two independent approaches: a) Direct inhibition of the alpha catalytic subunit of CK2, b) point directly to the acid domain of CK2 substrates (WO 03/054002 and Perea SE , et al., (2004) Antitumor effect of a novel proapoptotic peptide impairing the phosphorylation by the protein kinase CK2. Cancer Res. 64: 7127-7129). Using both approaches, the authors have demonstrated proof of the principle that inhibition of CK2 leads to apoptosis of tumor cells. These findings reinforce the experimental validation of CK2 as a suitable target to develop anticancer drugs.

Comparative proteomic studies together with studies in development with molecular biology have allowed, in part, the understanding of the molecular mechanisms involved both in the malignant transformation of cells and in tumor chemoresistance. Therefore, therapeutic regimens for cancer should focus their attention on achieving effective drug combinations that significantly reduce toxicity and also reduce the possibility of chemoresistance.

Therefore, one of the main objectives today in cancer therapy is to increase the therapeutic index of current cytostatic drugs by reducing the effective dose and intrinsic toxicity shown by this type of medication. Another current strategy is to avoid tumor chemoresistance towards conventional cytostatic drugs.

Detailed description of the invention

The present invention solves the problem mentioned above, since it provides a pharmaceutical combination containing two ingredients: a CK2 phosphorylation inhibitor (P15 peptide) and a pharmaceutically acceptable cytostatic drug.

In the present invention, "pharmaceutically acceptable cytostatic drug" refers to all compounds

Cytostatic chemicals used for cancer chemotherapy for solid tumors and for those of hematopoietic origin. Preferred cytostatics are cisplatin and carboplatin, paclitaxel and docetaxel, vincristine and vinblastine, 5-fluororacil, doxorubicin, cyclophosphamide, etoposide, mitomycin C, imatinib, iressa and velcade (bortezomib) mixed with suitable carriers.

Depending on the situation, the active ingredients of this pharmaceutical combination can be administered simultaneously, separately or sequentially. The administration of this pharmaceutical combination can be performed systemically, topically or orally. The present invention also relates to the treatment and / or drawing of chemoresistance in refractory tumors that occur in humans using the pharmaceutical combination mentioned above.

Also, the present invention relates to the use of the ingredients of this pharmaceutical combination to prepare a medicament for treating chemoresistant tumors and to increase the antitumor effect of the cytostatic drugs cited in the present invention.

Example 1 (Table 1) shows that the pharmaceutical combinations described in the present invention produce a synergistic antineoplastic effect in vitro. Therefore, the simultaneous combination of suboptimal doses of the P15 peptide together with cisplatin, paclitaxel, doxorubicin, vincristine, etoposide, mitomycin C, 5 fluorouracil, imatinib, or Iressa, achieves a 10 or 100-fold reduction in the effective dose for each drug. cytostatic mentioned in the present invention. The effective dose is the dose that reaches 50% of the antineoplastic effect, which is also called 50% inhibitory concentration (IC50), in in vitro proliferation assays in the present invention, "suboptimal doses" refers to a dose less than the IC50.

Example 2 illustrates the potentiation of the antitumor effect in vivo using this pharmaceutical combination containing the P15 peptide together with cisplatin (Figure 1A), cyclophosphamide (Figure 1B) and mitomycin C (Figure 1C). The pharmaceutical combination leads to the complete regression of the tumor in a relevant animal model such as that consisting of a human tumor xenografted in athymic mice. However, the use of the ingredients of this pharmaceutical combination as monotherapy produced a slight delay in tumor growth compared to the effect observed in the placebo-treated group.

The sequential administration of the ingredients of this pharmaceutical combination demonstrates that treatment with P15 prevents chemoresistance of the tumor both in vitro and in vivo. In the present invention, it is understood that "avoiding chemoresistance or chemosensitization" refers to the event of reducing the dose of drug necessary to produce 50% of the antitumor effect after pretreatment with the P15 peptide. Example 3 illustrates the effect of pretreatment with P15 peptide on the chemosensitization of tumor cells and produces a 10 to 100 fold reduction in the dose of effective drug. Similarly, the data shown in Table 3 represent that sequential administration of the pharmaceutical combination prevents intrinsic chemoresistance of tumor cells in vitro. In the present invention, in vitro chemoresistance is considered when the IC50 value reaches concentration values greater than 1,000

Similar to the in vitro results, pretreatment with the P15 peptide in vivo prevents intrinsic chemoresistance of the tumor (example 4) (Figure 2A, 2B, 2C).

Peptide ingredient P15 (amino acid sequence: CWMSPRHLGTC) has been previously reported as a CK2 inhibitor (Perea SE, et al., (2004) Antitumor effect of a novel proapoptotic peptide impairing the phosphorylation by the protein kinase CK2. Cancer Res. 64: 7127-7129). However, this peptide unexpectedly regulated a group of proteins on tumor cells (Table 4) that reinforces and explains the synergistic antitumor effect of the ingredients of the pharmaceutical combination, as well as the chemosensitization produced by pretreatment with the P15 peptide. For example, P15-regulated proteins play an essential role in the control of proliferation and apoptosis of tumor cells, and these mechanisms are not the same as those induced by the rest of the ingredients of this pharmaceutical combination, specifically the preferred cytostatic drug. in the present invention.

Likewise, other proteins that are regulated by the ingredient P15 are those involved in the molecular mechanisms of tumor chemoresistance of the preferred cytostatic drug in the present invention. These unexpected results constitute the molecular basis of tumor chemosensitization produced by this pharmaceutical combination when the ingredients are administered sequentially.

A characteristic feature of the present invention is the fact that effective concentrations of cytostatic drugs in the pharmaceutical combination are reduced from 10 to 100 times compared to the effective dose when cytostatic drugs are used alone. This means that a synergistic interaction occurs between the P15 CK2 inhibitor peptide and the preferred cytostatic drugs in the present invention. From a practical point of view, this synergistic interaction means that the toxicity of the drug based on this pharmaceutical combination is much lower than that observed for cytostatic drugs alone.

Similarly, the chemosensitization of the tumor caused after the sequential administration of the ingredients of this pharmaceutical combination represents a great advantage, since it allows treating the chemoresistance that is frequently observed in solid tumors and in those of hematopoietic origin.

Description of the figures:

Figure 1: Enhancement of the antitumor effect by the pharmaceutical combination in an animal cancer model: (A) represents the synergy between cisplatin + P15, (B) represents the synergy between cyclophosphamide + P15, (C) represents the in vivo synergy of mitomycin C + P15.

Figure 2: Effect of chemosensitization of the tumor by the P15 peptide in vivo: (A) represents the avoidance of chemoresistance towards cisplatin, (B) represents the avoidance of chemoresistance towards paclitaxel and (C) represents the avoidance of chemoresistance towards doxorubicin

Detailed statement of the examples

General Procedures:

Cell cultures: The H-125 cell line was obtained from a human amicrocytic lung carcinoma (NSCLC) and the SW948 cell line was obtained from a human colon carcinoma. Both cell lines are

kept in RPMI 1640 culture medium (Gibco) supplemented with 10% fetal bovine serum and gentamicin (50 g / ml). Cell cultures were incubated at 37 ° C in 5% CO2. Cell viability assay: For this purpose, 20 cells were added to the cells of each plate l tetrazolium (MTS) (Promega). After 2 hours at 37 ° C, the absorbance at 492 nm was measured. Finally, IC50 values were estimated from the corresponding dose-response curves using the "CurveExpert" software.

Animal cancer model: The animal model used in the present invention was based on the implantation of human tumors in nude mice (Nu / Nu, BALB / C). Briefly, 5x106 H-125 cells were suspended in phosphate buffered solution (PBS) and inoculated subcutaneously. Once the tumor was initiated (approximately 30 mm3), treatment was started using the pharmaceutical combination described in the present invention. To assess the antitumor effect of the pharmaceutical combination, the volume of the tumor mass was measured and the corresponding volume was calculated using the formula: V = width2 x length / 2.

Analysis of the protein profile in cell extracts: H-125 cells were treated or not with the P15 peptide ingredient of the pharmaceutical combination described in the present invention for 40 minutes. Then, the cell monolayers were washed with PBS and the cells were scraped off. Of the surface. After two additional washes with cold PBS, the cell pellets were resuspended in 10mM tris-HCl at pH 7.5, 0.25M sucrose, 1mM EGTA + protease inhibitor cocktail and the nuclear protein fraction was obtained as described. previously (González LJ, et al., (2003) Identification of nuclear proteins of small cell lung cancer cell line H82: An improved protocol for the analysis of silver stained proteins. Electrophoresis 24: 237252). To analyze the P15 regulated proteins, the corresponding nuclear protein extracts were alternatively resolved by 2D two-dimensional gels (pH 4-7) and / or liquid chromatography (nano HPLC) coupled to mass spectrometer.

The present invention is explained by the following examples:

Example 1: Synergistic effect of the combination of the P15 peptide + conventional cytostatic drugs

The antineoplastic synergistic effect between the P15 peptide ingredient combined with different cytostatic drugs was evaluated under the following experimental conditions: H-125 cells were seeded in 96-well plates and to each plate the P15 peptide was added at 10 and 50 M. Simultaneously , each of the preferred cytostatic drugs in the present invention was added at doses ranging from 1 to 2,000 nM and the incubation was prolonged for 72 hours under the same conditions. Finally, cell viability and IC50 values were determined as described previously in the present invention. The results shown in Table 1 demonstrate that the IC50 values for each cytostatic drug are reduced from 10 to 100 times when combined in a way concurrent with the ingredient P15 either at 10 or at 50 M. These results clearly demonstrate the potentiation of the antitumor effect of the pharmaceutical combination containing the P15 peptide and the preferred cytostatic drugs in the present invention as ingredients.

Table 1. Synergistic antineoplastic interaction by simultaneous administration of the ingredients in this pharmaceutical combination.

Variant

Cytostatic drug alone Cytostatic drug + P15 (90 M) Cytostatic drug + P15 (50 M)

Cisplatin

720 nM 530 nM 70nM

Paclitaxel

17 nM 8 nM 3 nM

5-Fluorouracil

1,200 nM 420 nM 60 nM

Vincristine

856 nM 100 nM 8 nM

Doxorubicin

423 nM 200 nM 76 Nm

Cyclophosphamide

2,400 nM 1004 nM 85 Nm

Mitomycin C

994 nM 93 nM 9 Nm

Imatinib

600 nM 200 nM 58 Nm

Velcade

2,000 nM 1,200 nM 700 Nm

Iressa

689 nM 174 nM 47 nM

Example 2: Enhancement of the antitumor effect by the pharmaceutical combination in an animal model of cancer.

For this purpose, 5x106 H-125 tumor cells were implanted as mentioned above in the present invention in BALB / C nude mice 6-8 weeks old. After starting the tumor, the 5 ingredients of the pharmaceutical combination were administered as follows: the P15 peptide in saline was administered intraperitoneally at 0.5 mg / kg / day for 5 days. Concomitantly, an intraperitoneal injection of cisplatin (Figure 1A) or cyclophosphamide (Figure 1B) or mitomycin (Figure 1C) was performed at 1 mg / kg / day on the same frequency. Cytostatic drugs are also suspended in saline. Tumor volume was recorded as described previously in the present invention. The results shown in Figures 1A, 1B and 1C indicate that the

The pharmaceutical combination potentiates the antitumor effect when the ingredients are administered simultaneously and as observed by complete tumor regression. Otherwise, when the ingredients are administered as monotherapy, only a slight antitumor effect was observed with respect to the placebo-treated group. Therefore, the authors also demonstrate the synergistic interaction between the ingredients of this pharmaceutical combination in an outstanding preclinical cancer model.

Example 3: Effect of peptide P15 in the avoidance of chemoresistance in vitro.

In this test, the inventors evaluated the effect of the pharmaceutical combination on the phenomenon of chemoresistance avoidance when the ingredients are administered sequentially. For this purpose, cells were seeded H-125 at 2,000 cells / well in 96-well plates and after 24 hours 20 M of the P15 peptide was added. After 16 hours of incubation with the P15 peptide ingredient, the cell monolayers were washed twice with saline. Finally, the preferred cytostatic drugs in the present invention were added at a concentration ranging from 1 to 2,000 nM and the incubation was prolonged for 72 hours. In the end, cell viability and IC50 values for each cytostatic drug were determined as previously described in the present invention. The results shown in Table 2 demonstrate that pretreatment of tumor cells with the peptide ingredient P15 increases the sensitivity of these cells to each of the preferred cytostatic drugs in the

25 present invention. In addition, the authors evaluated the effect of pretreatment with P15 on SW948 cells that are intrinsically resistant to the effect of cytostatic drugs. The results demonstrated that the ingredient peptide P15 also converts tumor cells refractory to the intrinsic drug into cells sensitive to the preferred cytostatic drugs in the present invention. (Table 3).

The data of the inventors demonstrate that the sequential administration of the P15 peptide ingredient with respect to

The preferred cytostatic drugs in the present invention leads to the sensitization of tumor cells to the antineoplastic effect of said drugs.

Table 2. In vitro chemosensitization of the pharmaceutical combination by sequential administration of the ingredients.

Variants

Cytostatic drug alone Cytostatic drug + pretreatment with P15

Cisplatin

720 nM 20 Nm

Paclitaxel

17 nM 0.9 nM

5-Fluorouracil

1,200 nM 105 nM

Vincristine

856 nM 83 nM

Doxorubicin

423 nM 72 nM

Cyclophosphamide

2,400 nM 100 nM

Mitomycin C

994 nM 20 nM

Imatinib

600 nM 10 nM

Velcade

2,000 nM 370 Nm

Iressa

689 nM 63 nM

Table 3. In vitro chemosensitization of the pharmaceutical combination by sequential administration of the ingredients on intrinsic drug refractory tumor cells.

Variants

Cytostatic drug alone Cytostatic drug + pretreatment with P15

Cisplatin

 1,000 m 120 m

Paclitaxel

 1,000 m 97 m

Doxorubicin

 1,000 m 320 M

The effect of the P15 peptide ingredient on chemosensitization is also verified by the drug-regulated protein profile observed in the tumor cells used in the present invention. For this purpose, nuclear protein extracts from H-125 cells treated or not treated with the peptide ingredient P15 were analyzed as previously described in the present invention. Table 4 shows a group of proteins that are regulated by the peptide ingredient P15 and by its known function, reinforces the molecular basis of the chemosensitization of the tumor produced by this peptide in the pharmaceutical combination in the present invention.

Table 4. Protein profile regulated by P15

Proteins regulated by decrease by the ingredient peptide P15

Rate of inhibition

Nucleophosmin

48

T-plasticine

3.34

Heat shock protein (HSP-27, -70 and -90)

2.5

Y-box 1 transcription factor

3.33

Erythropoietin precursor

120

S-glutathione transferase

4.87

Proteasome Activating Complex

3.35

Ubiquitin activated E1 enzyme

2.49

Glucose-6-phosphate isomerase

8.53

Glyceraldehyde-6-phosphate dehydrogenase

6.62

Pyruvate kinase

8.34

Tumor protein controlled during translation

4.32

Proteins regulated by increase by the ingredient peptide P15

Activation rate

Prohibitin

2.28

Tubulin alfa-1

3.23

Tubulin beta-2

2.56

Tubulin beta-3

3.15

Example 4: In vivo chemosensitization produced by the peptide ingredient P15

For this purpose, 5x106 SW948 cells were implanted in athymic mice as previously described in the present invention. After starting the tumor, the pharmaceutical combination was administered sequentially as follows: first, the peptide ingredient P15 was administered intraperitoneally at 0.5 mg / kg / day for 5 days. Then, cisplatin (Figure 2A), paclitaxel (Figure 2B) and doxorubicin (Figure 2C) were administered at 5 mg / kg / day for another 5 days. These results demonstrate that pretreatment in vivo with P15 can reverse the

Chemorefractory phenotype of tumors that become responsive to the preferred cytostatic drugs in the present invention. These findings also provide evidence that the pharmaceutical combination in the present invention can avoid the intrinsic tumor resistance commonly observed when the ingredients are administered sequentially.

Claims (8)

one.

 Pharmaceutical combination for simultaneous administration, separately or sequentially, containing a phosphorylation site peptide inhibitor on CK2 substrates together with a pharmaceutically acceptable cytostatic drug mixed with suitable carriers, in which the phosphorylation site peptide inhibitor on substrates of CK2 comprises peptide P15 (CWMSPRHLGTC).

2.

 The pharmaceutical combination according to claim 1, wherein the cytostatic drug is a chemical compound belonging to vinca platinum, taxoles and alkaloids.

3.

 The pharmaceutical combination according to claim 2, wherein said platinums are selected from carboplatin and cisplatin, said taxols are selected from paclitaxel and docetaxel, and said vinca alkaloids are selected from vincristine and vinblastine.

Four.

 The pharmaceutical combination according to claim 1, wherein the cytostatic drug is selected from 5-fluorouracil, doxorubicin, cyclophosphamide, mitomycin C, Velcade (bortezomib), Iressa and Imatinib.

5.

 A pharmaceutical combination according to any one of claims 1-4 for use in the treatment of cancer.

6.

 A pharmaceutical combination according to any one of claims 1-4 for use in the treatment of solid and hematopoietic tumors that are resistant to pharmaceutically acceptable cytostatic drugs and wherein the ingredients of the pharmaceutical combination are administered simultaneously, by separately or sequentially.

7.

 The pharmaceutical combination according to any one of claims 1-4 for use in the treatment of cancer according to claim 5 or for use in the treatment of solid and hematopoietic tumors according to claim 6, wherein The phosphorylation site inhibitor on CK2 substrates is a peptide.

8.

 The pharmaceutical combination according to any one of claims 1-4 for use in the treatment of cancer according to claim 6 or for use in the treatment of solid and hematopoietic tumors according to claim 7, wherein the phosphorylation site inhibitor on CK2 substrates is expressed in a DNA vector.

 Figure 1 Figure 2