Cancer treatment kit

Abstract

This invention provides a therapeutic agent that exhibits high anticancer activity against cancers, including ovarian clear cell carcinoma. [Solution] A cancer treatment kit comprising an (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonin. In the cancer treatment kit, the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor may be a GSK-3β inhibitor, and the GSK-3β inhibitor may be AR-A014418 (CAS number: 487021-52-3), and may be for the treatment of cancers exhibiting HNF-1β overexpression, or for the treatment of ovarian clear cell carcinoma.

Description

Technical Field

[0001] The present invention relates to a kit for cancer treatment.

Background Art

[0002] Ovarian clear cell carcinoma is a type of ovarian cancer and is so named because cancer cells show bright cytoplasm rich in glycogen. Ovarian clear cell carcinoma accounts for 6 - 8% of all ovarian cancers in Europe and the United States, but 24% in Japan, and is a frequently seen ovarian cancer in Japan. In addition, ovarian clear cell carcinoma often shows resistance to platinum preparations, which are standard in ovarian cancer treatment, and has a poor prognosis, so the development of effective therapeutic drugs is expected.

[0003] Hepatocyte nuclear factor 1β (HNF-1β) is a transcription factor with a homeodomain and is known to be overexpressed in ovarian clear cell carcinoma. HNF-1β is involved in cell proliferation, glucose metabolism, gene expression regulation, etc., and plays an important role in the survival and proliferation of ovarian clear cell carcinoma. Therefore, HNF-1β has been considered a promising target for ovarian clear cell carcinoma treatment. However, since HNF-1β is also expressed in organs such as the kidney, liver, pancreas, and digestive tract, there is a problem that there is a risk of serious side effects in inhibiting its activity.

[0004] Glycogen synthase kinase 3β (GSK-3β) is a protein kinase and is known to be involved in glycogen metabolism, cell cycle control, and cell proliferation. In recent years, a pathway in which GSK-3β is activated by HNF-1β and activates nuclear factor κB (NF-κB) has been discovered. It has been found that this pathway contributes to the survival of HNF-1β overexpressing cancer cells by GSK-3β, and it has attracted attention as a new target for cancer treatment.

[0005] Non-patent document 1 discloses that inhibiting GSK-3β in two types of renal cancer cell lines can suppress cancer cell proliferation and induce differentiation. In this study, pharmacological GSK-3β inhibition using maleimide-based GSK-3β inhibitors and genetic GSK-3β inhibition using siRNA were performed, and suppression of proliferation and induction of differentiation in renal cancer cell lines, as well as reduction of tumors introduced into nude mice, were confirmed in both cases. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Pal K, et al., Inhibition of GSK-3 induces differentiation and impaired glucose metabolism in renal cancer, Mol Cancer Ther., 13 (2), 285-296, 2014. [Overview of the project] [Problems that the invention aims to solve]

[0007] However, while Non-Patent Document 1 confirms the suppression of cancer cell line proliferation and tumor reduction, it does not lead to the elimination of cancer cell lines. The present invention aims to provide a therapeutic agent that exhibits high anticancer activity against HNF-1β-positive cancers, including ovarian clear cell carcinoma. [Means for solving the problem]

[0008] The present invention encompasses the following embodiments.

[0009] [1] A cancer treatment kit containing an (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4).

[0010] [2] The cancer treatment kit described in [1], wherein the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor is a GSK-3β inhibitor.

[0011] [3] The cancer treatment kit described in [2], wherein the GSK-3β inhibitor is AR-A014418 (CAS number: 487021-52-3).

[0012] [4] A cancer treatment kit described in any of [1] to [3], for the treatment of cancers exhibiting overexpression of HNF-1β.

[0013] [5] A cancer treatment kit relating to any of [1] to [4] for the treatment of ovarian clear cell carcinoma. [Effects of the Invention]

[0014] According to the present invention, it is possible to provide a therapeutic agent that exhibits a high anticancer effect against cancers, including ovarian clear cell carcinoma. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 is a graph showing the time course of confluence of TOV-21G cell lines in the control group and the GSK-3β interference group in Experiment Example 1. [Figure 2] Figure 2 is a graph showing the time course of confluence in the TOV-21G cell line for the actinonine group and the GSK-3β interference + actinonine group in Experiment Example 2. [Figure 3] Figure 3 is a graph showing the time course of confluence in the TOV-21G cell line in Experiment Example 3, for the control group, the GSK-3β inhibitor group, the actinonine group, and the GSK-3β inhibitor + actinonine combination group. [Figure 4] Figure 4 is a graph showing the time course of confluence in the TOV-21G cell line when the concentration of actinonine was kept constant and the concentration of the GSK-3β inhibitor was varied in Experiment Example 4. [Figure 5] Figure 5 is a graph showing the time course of confluence in the TOV-21G cell line when the concentration of actinonine was varied while the concentration of the GSK-3β inhibitor was kept constant in Experiment Example 5. [Figure 6] Figure 6 is a schematic diagram of the procedure of an animal experiment using a GSK-3β inhibitor and actinonin in combination with an ovarian cancer model mouse in Experimental Example 6. [Figure 7] Figure 7 is a photograph comparing the tumors of the control group and the group treated with a combination of a GSK-3β inhibitor and actinonin in Experimental Example 6. [Figure 8] Figure 8 is a graph comparing the total tumor weight, body weight loss rate, and blood test values of the control group and the group treated with a combination of a GSK-3β inhibitor and actinonin in Experimental Example 6. [Figure 9] Figure 9 is a photograph of TOV-21G cells when a GSK-3β inhibitor and actinonin are used in combination and when only actinonin is used in Experimental Example 7. [Figure 10] Figure 10 is a graph showing the time change in confluency of cell lines of the control group, the GSK-3β inhibitor administration group, the actinonin administration group, and the GSK-3β inhibitor + actinonin combination group using 769-P and 786-O, which are cell lines of clear cell renal carcinoma, in Experimental Example 8.

Mode for Carrying Out the Invention

[0016] Hereinafter, an embodiment of the present invention will be described. The embodiments shown below are examples of configurations for embodying the technical idea of the present invention, and the present invention is not limited by the following embodiments. Various changes can be made within the technical scope defined by the claims described in the claims of the present invention's technical idea.

[0017] (Kit for Cancer Treatment) The cancer treatment kit of the present embodiment contains a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonin. That the cancer treatment kit contains a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonin may mean that the cancer treatment kit is in the form of a pharmaceutical composition, and the pharmaceutical composition contains a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonin. Alternatively, the cancer treatment kit may contain a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonin, each stored in a separate container, and they are provided in a form for combined use.

[0018] ((HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor) (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor may be a substance that inhibits the activity of at least one molecule on the (HNF-1β)-(GSK-3β)-(NF-κB) pathway, or a substance that suppresses the expression of at least one molecule on the pathway. Among them, those that selectively inhibit the activity of GSK-3β (GSK-3β inhibitors) are preferred. Examples of the GSK-3β inhibitor include AR-A014418 (CAS number: 487021-52-3), SB216763 (CAS number: 280744-09-4), and Elraglusib (CAS number: 1034895-42-5).

[0019] When GSK-3β is inhibited, glycogen synthase, which has been phosphorylated and inactivated by GSK-3β, is activated, and glucose metabolism (glycolysis) in cells is suppressed. In Non-Patent Document 1, it was confirmed that the growth of cancer cells can be suppressed by inhibiting GSK-3β, but the GSK-3β inhibitor alone has not been able to show a sufficient antitumor effect.

[0020] The inventors have found that combining a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor, including a GSK-3β inhibitor, with actinonine enhances the antitumor effect, exhibiting a potent antitumor effect not seen with the GSK-3β inhibitor alone. Furthermore, experiments using model mice have shown that the combination of the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine suppresses the number and total weight of tumors in vivo.

[0021] In the cancer treatment kit of this embodiment, the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor may be formulated as a pharmaceutical composition containing a pharmaceutically acceptable carrier.

[0022] The pharmaceutical composition may be in a dosage form for oral use or a dosage form for parenteral use. Examples of orally used dosage forms include tablets, capsules, elixirs, and microcapsules. Examples of parenteral use dosage forms include injections, inhalants, suppositories, and patches.

[0023] Examples of pharmaceutically acceptable carriers include solvents such as sterile water and physiological saline; binders such as gelatin, corn starch, tragacanth gum, and gum arabic; excipients such as crystalline cellulose; and leavening agents such as alginic acid.

[0024] The pharmaceutical composition may further contain additives. Examples of additives include lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, and saccharin; flavoring agents such as peppermint and red ginger oil; stabilizers such as benzyl alcohol and phenol; buffering agents such as phosphates and sodium acetate; solubilizers such as benzyl benzoate and benzyl alcohol; antioxidants; and preservatives.

[0025] The pharmaceutical composition can be formulated by appropriately combining the above-mentioned carriers and additives and mixing them in a unit dose form generally accepted for pharmaceutical production.

[0026] The drug can be administered to patients by methods known to those skilled in the art, such as intra-arterial injection, intravenous injection, subcutaneous injection, as well as intranasal, transbronchial, intramuscular, transcutaneous, or oral administration. The dosage will vary depending on the patient's weight, age, symptoms, and method of administration, but those skilled in the art can appropriately select a suitable dosage.

[0027] The dosage of (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitors varies depending on the type of (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and the patient's symptoms. However, for oral administration, it is generally considered appropriate for adults (assuming a body weight of 60 kg) to administer approximately 0.1 to 500 mg per day, preferably approximately 1.0 to 250 mg, and more preferably approximately 1.0 to 100 mg, once a day or in several divided doses.

[0028] When administered parenterally, the dosage varies depending on the type of (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor, the patient's symptoms, the target organ, and the method of administration. However, when administered systemically, it is generally considered appropriate for an adult (assuming a body weight of 60 kg) to administer approximately 0.1 to 500 mg per day, preferably approximately 1.0 to 250 mg, and more preferably approximately 1.0 to 100 mg, once or in several divided doses per day. When administered locally, it is generally considered appropriate for an adult (assuming a body weight of 60 kg) to administer approximately 0.001 to 10 mg per day, preferably approximately 0.01 to 5 mg, and more preferably approximately 0.02 to 2 mg, once or in several divided doses per day.

[0029] (Actinonine) Actinonine is a natural antimicrobial agent that inhibits prokaryotic protein synthesis by inhibiting the activity of peptide deformidase. In humans, peptide deformidase is localized only in mitochondria, and it is known that administration of actinonine can suppress the proliferation of cancer cells. However, there was a problem in that administration of actinonine alone did not provide a sufficient antitumor effect.

[0030] The inventors have found that combining actinonine with a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor containing a GSK-3β inhibitor enhances the antitumor effect, exhibiting a potent antitumor effect not seen with actinonine alone. Actinonine and the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor may be administered in either order, or both may be administered simultaneously.

[0031] Actinonine may also be in the form of a salt. Any pharmaceutically acceptable salt of actinonine can be selected as appropriate. In addition, various derivatives of actinonine can be selected as long as they are within the pharmaceutically and physiologically acceptable range and do not reduce the pharmacological effect.

[0032] In the cancer treatment kit of this embodiment, actinonine may be formulated as a pharmaceutical composition containing a pharmaceutically acceptable carrier. The dosage form, pharmaceutically acceptable carrier, and route of administration are the same as those described above for (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitors.

[0033] The dosage of actinonine varies depending on the patient's symptoms, but for oral administration, it is generally considered appropriate for adults (weighing 60 kg) to administer approximately 0.1 to 3,000 mg per day, preferably approximately 1.0 to 2,000 mg, and more preferably approximately 1.0 to 1,000 mg, once a day or in several divided doses.

[0034] When administered parenterally, the dosage will vary depending on the patient's symptoms, target organ, and method of administration. However, for systemic administration, it is generally considered appropriate for an adult (assuming a body weight of 60 kg) to administer approximately 0.1 to 1,500 mg per day, preferably approximately 1.0 to 1,000 mg, and more preferably approximately 1.0 to 500 mg, once or in several divided doses per day. For local administration, it is generally considered appropriate for an adult (assuming a body weight of 60 kg) to administer approximately 0.001 to 30 mg per day, preferably approximately 0.01 to 20 mg, and more preferably approximately 0.02 to 10 mg, once or in several divided doses per day.

[0035] (Cancers targeted by cancer treatment kits) The cancer treatment kit of this embodiment is effective against cancers in which at least one molecule of the (HNF-1β)-(GSK-3β)-(NF-κB) pathway is overexpressed, and is particularly effective against cancers that show overexpression of HNF-1β. Examples of cancers that show overexpression of HNF-1β include ovarian clear cell carcinoma, renal cancer, and colorectal cancer.

[0036] (Other embodiments) In one embodiment, the present invention provides a method for treating cancer, comprising administering an effective amount of a combination of a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4) to a patient in need of treatment.

[0037] In one embodiment, the present invention provides a combination of a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4) for use in the treatment of cancer.

[0038] In one embodiment, the present invention provides the use of a combination of a (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4) for the manufacture of a cancer therapeutic agent.

[0039] In each of these embodiments, the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor, actinonine, formulation of these drugs, dosage of these drugs, and target cancers are the same as described above. [Examples]

[0040] The present invention will be described below with reference to examples, but the present invention is not limited to these examples and can be implemented with appropriate modifications without changing the essence of the invention.

[0041] (Experimental Example 1) The TOV-21G cell line, a clear cell carcinoma cell line from the ovary, was cultured and dispensed into 96-well plates. The dispensed TOV-21G cell lines were divided into a control group and a GSK-3β interference group. The medium for the GSK-3β interference group was treated with si-GSK-3β (Horizon Discovery, #D-003010-09) at a concentration of 15 nM. The medium for the control group was treated with si-control (Horizon Discovery, #D-001206-14) at the same concentration. Both the control group and the GSK-3β interference group were imaged every 3 hours for approximately 150 hours using an incubator (Sartorius), and the time-dependent changes in confluence were measured. The results are shown in Figure 1.

[0042] Figure 1 shows a graph illustrating the time course of confluence of TOV-21G cell lines in the control group and the GSK-3β interference group. Although the proliferation rate in the GSK-3β interference group decreased compared to the control group due to the GSK-3β inhibitor, both groups eventually reached confluence. This result confirms that GSK-3β inhibitors alone have insufficient antitumor effect against ovarian clear cell carcinoma cell lines.

[0043] (Experimental Example 2) The control group and the GSK-3β interference group, cultured and dispensed in the same manner as in Experimental Example 1, were further administered with actinonine to a concentration of 50 μM. The actinonine group (administered with actinonine alone) and the GSK-3β interference + actinonine group (administered with both GSK-3β interference and actinonine) were imaged using an incubator every 3 hours for approximately 100 hours, and the time-dependent changes in confluence were measured. The si-GSK-3β (Horizon Discovery, #D-003010-09) concentration administered to the GSK-3β interference + actinonine group was varied to 5 nM, 10 nM, 15 nM, and 20 nM, and the results were compared. The actinonine group was administered si-control (Horizon Discovery, #D-001206-14) at the same concentration instead of si-GSK-3β. The results are shown in Figure 2.

[0044] Figure 2 shows a graph illustrating the time course of confluence in TOV-21G cell lines in the actinonine group and the GSK-3β interference + actinonine group. While confluence continued to increase with actinonine alone, in the GSK-3β interference + actinonine group, confluence initially increased but then decreased at all GSK-3β inhibitor concentrations, and continued to decrease throughout the time period. This result indicates that a potent antitumor effect can be obtained by combining GSK-3β interference with actinonine.

[0045] In addition to the combination of GSK-3β interference and actinonine, a similarly potent antitumor effect was observed with the combination of HNF-1β interference and actinonine. These results indicate that while actinonine alone does not provide sufficient antitumor effects, a strong antitumor effect can be obtained by combining an inhibitor of the (HNF-1β)-(GSK-3β)-(NF-κB) pathway with actinonine.

[0046] (Experimental Example 3) To compare the antitumor effects of GSK-3β inhibitors and actinonine, the following experiment was conducted. In this experiment, TOV-21G cell lines were divided into a control group, an actinonine group, a GSK-3β inhibitor group, and a GSK-3β inhibitor + actinonine group. The actinonine group was administered actinonine to a concentration of 50 μM. The GSK-3β inhibitor group was administered GSK-3β inhibitor to a concentration of 20 μM. Dimethyl sulfoxide was administered to the actinonine group at the same concentration instead of GSK-3β inhibitor. Dimethyl sulfoxide was administered to the GSK-3β inhibitor group at the same concentration instead of actinonine. AR-A014418 was used as the GSK-3β inhibitor. The GSK-3β inhibitor + actinonine group was administered actinonine to a concentration of 50 μM and GSK-3β inhibitor to a concentration of 20 μM. Subsequently, the time course of confluence was observed. Incubators were used for observation, and each group was observed every three hours for 300 hours.

[0047] Figure 3 shows the results. In the control group, the increase continued until confluence was reached. In the GSK-3β inhibitor monotherapy group, the increase initially reached subconfluence before decreasing. In the actinonine monotherapy group, the rate of increase was suppressed, but the increase continued slowly. In contrast, in the GSK-3β inhibitor + actinonine combination group, the increase was initially followed by a decrease, and ultimately the cancer cells were killed. The combination of GSK-3β interference and actinonine demonstrated a rapid and potent antitumor effect.

[0048] (Experimental Example 4) The effect of GSK-3β inhibitor concentrations on a constant actinonine concentration was evaluated. TOV-21G cell lines were simultaneously administered a GSK-3β inhibitor and actinonine. The actinonine concentration was set to 50 μM. GSK-3β inhibitor concentrations were set to 2.5 μM, 5 μM, 10 μM, 20 μM, 40 μM, and 80 μM. AR-A014418 was used as the GSK-3β inhibitor. The time course of confluence was recorded for each GSK-3β inhibitor concentration.

[0049] Figure 4 is a graph showing the time course of TOV-21G confluence when the concentration of the GSK-3β inhibitor was varied while the actinonine concentration was kept constant. A concentration-dependent inhibitory effect on TOV-21G proliferation was observed with the GSK-3β inhibitor, and TOV-21G death was observed at all GSK-3β inhibitor concentrations. These results clearly demonstrate that when used in combination with actinonine, the GSK-3β inhibitor exhibits a potent antitumor effect at all concentrations.

[0050] (Experimental Example 5) The effect of actinonine concentration was evaluated when the GSK-3β inhibitor concentration was kept constant. Similar to Experimental Example 4, TOV-21G cell lines were simultaneously administered a GSK-3β inhibitor and actinonine. The GSK-3β inhibitor concentration was set to 20 μM. AR-A014418 was used as the GSK-3β inhibitor. Actinonine concentrations were set to 6.25 μM, 12.5 μM, 25 μM, 50 μM, 100 μM, and 200 μM. The time course of confluence was recorded for each actinonine concentration.

[0051] Figure 5 is a graph showing the time course of TOV-21G confluence when the actinonine concentration was varied while the GSK-3β inhibitor concentration was kept constant. A growth inhibitory effect on TOV-21G was observed in an actinonine concentration-dependent manner, and TOV-21G death was observed at all actinonine concentrations. These results clearly demonstrate that actinonine exhibits a potent antitumor effect at all concentrations when used in combination with a GSK-3β inhibitor.

[0052] (Experimental Example 6) Next, the antitumor effect of a combination of a GSK-3β inhibitor and actinonin was investigated using ovarian cancer model mice. Figure 6 is a schematic diagram of the experiment using ovarian cancer model mice. TOV-21G approximately 7.5 × 10 6 The cells were suspended in 200 μL of PBS and seeded into the peritoneal cavity of 5-week-old female nude mice to create ovarian cancer model mice. The ovarian cancer model mice were divided into a control group and a group administered a GSK-3β inhibitor and actinonine.

[0053] The GSK-3β inhibitor and actinonine administration groups received a GSK-3β inhibitor (AR-A014418, concentration 4 mg / kg) mixed with corn oil, and actinonine dissolved in dimethyl sulfoxide using liposomal technology (final concentration 10 mg / kg, assuming 50% encapsulation). The control group received the same volume of dimethyl sulfoxide dissolved in corn oil instead of the GSK-3β inhibitor, and the same volume of dimethyl sulfoxide encapsulated in liposomes instead of actinonine. After 17 days, the ovarian cancer model mice were euthanized, and the number and location of tumors, tumor weight, body weight, and blood test values ​​were compared.

[0054] Figure 7 shows a comparison of tumors in the control group and the group treated with GSK-3β inhibitors and actinonine. In the control group, many disseminated lesions were observed in the peritoneum and omentum of the pelvis, while almost no tumors were observed in the group treated with GSK-3β inhibitors and actinonine.

[0055] Figure 8 shows graphs of total tumor weight, weight loss rate, and blood test values ​​in the control group and the GSK-3β inhibitor and actinonine administration group. Total tumor weight was significantly lower in the GSK-3β inhibitor and actinonine administration group compared to the control group (GSK-3β inhibitor and actinonine administration group: 170.0±29.7 mg, control group: 417.0±170.0 mg, p=0.014). There was no significant difference in weight loss rate between the two groups. This result indicates that no serious side effects were observed with the administration of GSK-3β inhibitors and actinonine. Blood tests measured urea nitrogen, creatinine, and ALT as markers of liver and kidney function. There were no significant differences in blood test values ​​between the two groups. This result further supports the conclusion that no serious liver or kidney side effects were observed with the administration of GSK-3β inhibitors and actinonine.

[0056] (Experimental Example 7) (Imaging of ovarian clear cell carcinoma cells) Ovarian clear cell carcinoma cell line TOV-21G was exposed to actinonine alone or in combination with a GSK-3β inhibitor and actinonine, and photographed with a light microscope after a certain period of time. AR-A014418 was used as the GSK-3β inhibitor. Figure 9 shows the photographs taken. Compared to the case where actinonine was used alone, it was confirmed that the ovarian clear cell carcinoma cells were clearly atrophied and killed when both were used.

[0057] (Experimental Example 8) The renal clear cell carcinoma cell lines 769-P and 786-O are HNF-1β positive cell lines. These cells were divided into control, actinonine, GSK-3β inhibitor, and GSK-3β inhibitor + actinonine groups, and administered the drugs as in Experimental Example 3. The time-dependent changes in confluence of the 769-P and 786-O cell lines were observed. The actinonine group received dimethyl sulfoxide at the same concentration as the GSK-3β inhibitor. The GSK-3β inhibitor group received dimethyl sulfoxide at the same concentration as the actinonine. AR-A014418 was used as the GSK-3β inhibitor. In the 769-P cell line, actinonine was administered at 20 μM and the GSK-3β inhibitor at 30 μM. In the 786-O cell line, actinonine was administered at 50 μM and the GSK-3β inhibitor at 25 μM.

[0058] The results of Experimental Example 8 are shown in Figure 10. Figure 10 is a graph showing the time change in confluence for each group in 769-P and 786-O. In 769-P, the actinonine monotherapy group was similar to the control group. Tumor growth was suppressed with GSK-3β inhibitor monotherapy compared to the control group, but a further suppressive effect was observed in the GSK-3β inhibitor + actinonine group. In 786-O, tumor growth increased to subconfluence in both the control and actinonine groups, while GSK-3β inhibitors suppressed tumor growth but showed a tendency towards proliferation, and the GSK-3β inhibitor + actinonine group reached a plateau. From these results, it is clear that GSK-3β inhibitors exhibit a potent antitumor effect when used in combination with actinonine.

[0059] These results demonstrate that a cancer treatment kit containing the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4) exhibits high antitumor efficacy, is effective against ovarian clear cell carcinoma, and also possesses high safety. [Industrial applicability]

[0060] According to the present invention, it is possible to provide a therapeutic agent that exhibits high anticancer activity across tumors against HNF-1β-positive cancers such as ovarian clear cell cancer.

Claims

1. A cancer treatment kit containing an (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor and actinonine (CAS number: 13434-13-4).

2. The cancer treatment kit according to claim 1, wherein the (HNF-1β)-(GSK-3β)-(NF-κB) pathway inhibitor is a GSK-3β inhibitor.

3. The cancer treatment kit according to claim 2, wherein the GSK-3β inhibitor is AR-A014418 (CAS number: 487021-52-3).

4. A cancer treatment kit according to any one of claims 1 to 3, for the treatment of cancer exhibiting overexpression of HNF-1β.

5. A cancer treatment kit according to any one of claims 1 to 3, for the treatment of ovarian clear cell carcinoma.

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