JP2010111582A - Therapeutic agent for liver cancer comprising rifampicin as component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a therapeutic agent for liver cancer that comprises rifampicin or its derivative as an active ingredient. <P>SOLUTION: An extensive study was made for the purpose of developing a therapeutic agent for liver cancer. As a consequence, it is found that rifampicin or a derivative thereof has a therapeutic effect on liver cancer, particularly metastatic liver cancer. Rifampicin or a derivative thereof has an action of suppressing the proliferation of cancer metastasized to the liver and the invasion of the cancer into a liver tissue, and has a therapeutic effect on metastatic liver cancer. Rifampicin or a derivative thereof is useful as a therapeutic agent for metastatic liver cancer or an active ingredient of an inhibitor of cancer metastasis to the liver. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a liver cancer therapeutic agent comprising rifampicin or a derivative thereof as an active ingredient.

The following findings regarding rifampicin have been reported.
(1) Antibacterial action Rifampicin was developed as an anti-tuberculosis antibiotic. Rifampicin binds to the β subunit of the DNA-dependent RNA polymerase encoded by the prokaryotic rpoB gene and exhibits antibacterial activity by inhibiting RNA synthesis.

(2) Chemical structure

3-[[(4-methyl-1-piperazinyl) imino] methyl)] rifamycin 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22 -heptamethyl-8- [N- (4-methyl-1-piperazinyl) formimidoyl] 2,7- (epoxypentadecal [1,11,13] trienimino) -naphtho [2,1-beta] furan-1,11 (2H ) -dione 21-acetate
C ₄₃ H ₅₈ N ₄ O ₁₂ : 822.95
One of the chemical structural features of rifampicin is the presence of the naphtohydroquinone structure, which contributes to the action of rifampicin as a free radical scavenger (radical scavenger). Conceivable.

(3) Free radical removal action
(a) ONOO ⁼ suppression:
Nitric oxide (NO) plays an important role in the body, such as vasodilatory action, but when present in large quantities, it combines with oxygen and changes to peroxynitrite (ONOO ⁼ ). ONOO ⁼ oxidizes biological substances such as lipids, proteins, and DNA, and causes nitritation of tyrosine, causing injury (see Non-Patent Document 1). Both tyrosine and α1-antiproteinase are associated with inflammatory responses, and their nitritation causes inflammatory responses. Rifampicin suppressed nitritation of these substances (see Non-Patent Document 2).

(b) Antioxidant action:
DPPH (α, α-diphenil-β-picryl hydrazyl) is a stable radical, which was used to evaluate the antioxidant activity of the compound. As a result, it was found that rifampicin has an antioxidant effect (see Non-Patent Document 3).

(c) Amyloid aggregation inhibitory action:
A soluble amyloid β protein (Aβ) aggregated and insolubilized causes Alzheimer's disease. When examined with a system using Aβ1-40 peptide, rifampicin inhibited the aggregation reaction. It is known that free radicals that have appeared in the aggregation reaction of Aβ1-40 peptide play a large role, and it is assumed that the free radical removal action of rifampicin is involved in the suppression of the aggregation reaction (Non-patent Document 4). reference).

(4) Tissue distribution:
The distribution of rifampicin in various tissues was performed by taking the tissue by biopsy after administration of 150 mg and 450 mg. In terms of the blood / tissue concentration ratio, at 12 hours after administration, the bile, liver, gallbladder wall, ureter, and ovarian cyst wall are less than 1 (ie, the tissue concentration is high) Close to 1 were the spleen, mesenteric sac and fluid, appendix, skin, muscle, bone and breast cancer tissue, and those greater than 1 were lung, stomach wall and stomach cancer tissue, fat and milk. In particular, it is characterized by accumulating in the liver by reabsorption from the bile in the liver (see Non-Patent Document 5).

(5) Angiogenesis inhibitory action:
Rifampicin and its derivatives have been reported to have an anti-angiogenic effect (see Patent Document 1).

(6) Anticancer action:
It has been reported that rifampicin or its derivatives have weak anticancer activity against cultured cancer cells. In clinical practice, there is a report that the prognosis of patients improves when administered to patients with cholangiocarcinoma. In rat adenocarcinoma, the administration of rifampicin derivative via the abdominal cavity was found to have an anticancer effect, but was not effective by oral or transdermal administration. The possibility that rifampicin suppresses recurrence of acute myeloid leukemia has been pointed out (see Non-Patent Documents 6 to 12).

Patent Publication No. 2004-75665 Nao Fujita, “Generation and elimination mechanism of active oxygen, lipid peroxide, and free radicals and their biological effects”, Pharmaceutical Journal, 2002, Vol.122, p.203-218 Whiteman, M. and Halliwell, B., "Prevention of peroxynitrite-dependent tyrosine nitration and inactivation of alpha1-antiproteinase by antibiotics.", Free Radic Res, 1997, Vol. 26, p.49-56. Kalpana, T. and 4 other authors, "Assessment of antioxidant activity of some antileprotic drugs.", Arzneimittelforschung, 2001, Vol.51, p.633-637 Tomiyama, T. and 6 others, “Inhibition of amyloid beta protein aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger.”, J Biol Chem, 1996, Vol.271, p.6839-6844 Acocella, G., "Clinical pharmacokinetics of rifampicin.", Clin Pharmacokinet, 1978, Vol. 3, p.108-127 Winters, W. D. and two other authors, "Differential effects of rifampicin on cultured human tumor cells.", Cancer Res, 1974, Vol. 34, p. 3173-3179 Joss, U. R. and two other authors, "Effect of dimethylbenzyldesmethylrifampicin (DMB) on chemically induced mammary tumours in rats.", Nat New Biol, 1973, Vol.242, p.88-90 Sali, A. 3 other authors, “Rifampicin as cytotoxic agent for cholangiocarcinoma: preliminary report of seven cases.”, J Cancer Res Clin Oncol, 1991, Vol. 117, p.503-504 Burghouts, J. and Haanen, C., `` A possible role of rifampicin in prolonging remission duration in acute myelogenous leukaemia. '', Scand J Haematol, 1986, Vol. 36, p.376-378 Adamson, R. H., "Evaluation of the antitumor activity of rifamycin SV.", Arch Int Pharmacodyn Ther, 1971, Vol.192, p.61-65 Hughes, A. M. and Calvin, M., "Effect of some rifamycin derivatives on chemically-induced mammary tumors in rats.", Cancer Lett, 1976, Vol. 2, p. 5-10 Hughes, A. M. and five other authors, “Inhibition of adenocarcinoma TA3 ascites tumor growth by rifamycin derivatives.”, Oncology, 1978, Vol. 35, p.76-82

  An object of the present invention is to provide a therapeutic agent for liver cancer. Another object is to provide a therapeutic agent for metastatic liver cancer and a cancer metastasis inhibitor to the liver.

As a result of intensive studies to solve the above problems, the present inventors have found that rifampicin or a derivative thereof has a therapeutic effect on liver cancer.
Gastric cancer, colorectal cancer, and lung cancer are all cancers common to Japanese people, but they often metastasize to the liver via the portal vein after surgery. The present inventors have intensively studied to develop a therapeutic agent for liver cancer metastasized from other organs, and have found that rifampicin or a derivative thereof has a therapeutic effect on metastatic liver cancer.
Rifampicin or a derivative thereof has an action of suppressing the growth of various cancers that have metastasized to the liver and infiltration into the liver tissue, and has a therapeutic effect on liver cancer, particularly metastatic liver cancer.

As described above, rifampicin has been reported to have anticancer activity against cholangiocarcinoma, but it has not been reported that rifampicin or a derivative thereof is effective against liver cancer, particularly hepatoma.
Adriacin, an anticancer drug, has been reported to be 16.7% in clinical trials for liver cancer, whereas it has 60% effect on gallbladder cancer and bile duct cancer (Masaka Yokoyama, Satoshi Takamori) Shigeki Ujiie, Tatsuo Saito (1974) Treatment of malignant tumors with Adriamycin Cancer Clinic Volume 20, No. 7, 536-544). As shown in the findings, cholangiocarcinoma and hepatoma are different types of cytologically, and generally, the type of anticancer agent is different if the type of cancer cell is different. That is, even if it is known that rifampicin is effective for cholangiocarcinoma, it cannot be predicted to be effective for hepatocellular carcinoma as well.
Moreover, it is the knowledge discovered for the first time by this inventor that it has an effective therapeutic effect with respect to the metastatic cancer to a liver.
Rifampicin or a derivative thereof is useful as an active ingredient of a therapeutic agent for liver cancer, particularly a therapeutic agent for metastatic liver cancer, or an inhibitor of cancer metastasis to the liver.

That is, the present invention relates to a therapeutic agent for liver cancer, particularly a therapeutic agent for metastatic liver cancer, and a cancer metastasis inhibitor to the liver, more specifically,
[1] A therapeutic agent for liver cancer comprising rifampicin or a derivative thereof as an active ingredient,
[2] The therapeutic agent according to [1], wherein the liver cancer is hepatoma cell carcinoma,
[3] The therapeutic agent according to [1], wherein the liver cancer is metastatic liver cancer,
[4] The therapeutic agent according to [3], wherein the metastatic liver cancer is lung cancer, gastric cancer, rectal cancer, colon cancer, colon cancer, pancreatic cancer, or metastatic cancer from breast cancer,
[5] A cancer metastasis inhibitor comprising rifampicin or a derivative thereof as an active ingredient,
[6] The cancer metastasis inhibitor according to [5], wherein the cancer metastasis is cancer metastasis to the liver,
[7] The cancer metastasis inhibitor according to [6], wherein the cancer metastasis is lung cancer, gastric cancer, rectal cancer, colon cancer, colon cancer, pancreatic cancer, or breast cancer metastasis to the liver,
Is provided.

The present invention relates to the use of rifampicin or a derivative thereof for the treatment of liver cancer, particularly cancer that has metastasized to the liver.
Rifampicin has a high degree of accumulation in the liver and is therefore expected to be effective for cancer that has metastasized to the liver. Rifampicin is a free radical scavenger, but it is known that free radical scavenger has an activity to block invasion and migration of cancer cells in the liver, and rifampicin and its derivatives suppress angiogenesis. It is expected to suppress cancer growth as a result. In addition, the action as a free radical scavenger of rifampicin may contribute to the angiogenesis inhibitory action.
The present inventor has found that rifampicin or a derivative thereof has an action of suppressing the growth of liver cancer, particularly various cancers that have metastasized to the liver, and infiltration into the liver tissue, and can be used as a therapeutic agent thereof.

The present inventor has found that rifampicin or a derivative thereof has an anticancer activity against liver cancer, particularly metastatic liver cancer. The present invention relates to a therapeutic agent for liver cancer comprising rifampicin or a derivative thereof as an active ingredient.
A preferred embodiment of the therapeutic agent of the present invention is a therapeutic agent for hepatocellular carcinoma. The present invention also provides a therapeutic agent for metastatic liver cancer comprising rifampicin or a derivative thereof as an active ingredient.

Furthermore, the present inventors have found that rifampicin or a derivative thereof suppresses the metastasis of cancer originating from organs other than the liver to the liver. That is, the present invention relates to an agent for suppressing cancer metastasis to the liver, comprising rifampicin or a derivative thereof as an active ingredient. (In the present specification, the therapeutic agent or cancer metastasis inhibitor of the present invention may be simply referred to as “the drug of the present invention”).
The active ingredient of the drug of the present invention is usually a compound represented by the following general formula (I).

A preferred embodiment of the present invention is a drug containing a derivative of the compound represented by the general formula (I) as an active ingredient.
Examples of the derivatives of rifampicin that can be used as the drug of the present invention include 3-Folmyl-RFM, Rifamycin SV, or the main metabolite 25-Desacetyl-RFP.

  In the present invention, “metastatic liver cancer” refers to liver cancer that originates in an organ or tissue other than the liver, and usually refers to cancer in which cancer in an organ or tissue other than the liver has metastasized to the liver. For example, liver cancer caused by cancer that has occurred in the lung, stomach, rectum, large intestine, colon, pancreas, or mammary gland (eg lung cancer, stomach cancer, rectal cancer, colon cancer, colon cancer, pancreatic cancer, breast cancer, etc.) metastasized to the liver Is mentioned.

  In the present invention, a salt of rifampicin is also included in the derivatives of the present invention. In the present invention, the “salt” is not particularly limited as long as it forms a salt with the rifampicin of the present invention and is pharmacologically acceptable, and examples thereof include inorganic acid salts, organic acid salts, inorganic base salts, Organic base salts, acidic or basic amino acid salts and the like can be mentioned. In the present invention, “salt” usually refers to a pharmaceutically acceptable salt.

The therapeutic agent of the present invention can also be expressed as, for example, “therapeutic agent”, “anticancer agent”, “antitumor agent”, “composition for cancer treatment”, “pharmaceutical agent”, “pharmaceutical composition” and the like.
The therapeutic agent of the present invention usually refers to a drug (medicine, pharmaceutical composition) having an effect of treating cancer or suppressing cancer metastasis. For example, it has an effect of preventing cancer or preventing cancer metastasis. The drug having is also included in the drug of the present invention.

  In the present invention, “cancer” is usually also referred to as a malignant tumor.

  A drug containing rifampicin or a derivative thereof of the present invention as an active ingredient is prepared by a conventional method using tablets, pills, powders, fine granules, granules, powders, coated tablets, capsules, inhalants, suppositories, injections. It can be formulated as an agent, ointment, liquid, emulsion, suspension, injection or the like.

  Commonly used excipients, binders, lubricants, colorants, flavoring agents, and stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives as necessary Antioxidants and the like can be used, and they are generally formulated by blending ingredients used as raw materials for pharmaceutical preparations.

  For example, in order to produce an oral preparation, the compound according to the present invention or a pharmacologically acceptable salt and excipient thereof, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a flavoring agent. After adding, etc., it is made into powders, fine granules, granules, tablets, coated tablets, capsules and the like by conventional methods.

  When preparing a liquid preparation such as an injectable preparation, the compound according to the present invention or a pharmacologically acceptable salt thereof is dissolved in a pH adjuster, a solubilizer, an isotonic agent, etc. as necessary. Add adjuvants, stabilizers, etc., and formulate in a conventional manner. When preparing an injection, a pH adjusting agent, a buffer, a stabilizer, a preservative, etc. are added as necessary, and a subcutaneous, intramuscular or intravenous injection is prepared by a conventional method. The injection may be prepared as a solid preparation by lyophilization after storing the solution in a container.

As a base material used for formulation, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics, and the like can be used. Specific examples of base materials to be used include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, Examples include raw materials such as water-soluble polymers, clay minerals, and purified water. If necessary, add pH adjusters, antioxidants, chelating agents, antiseptic / antifungal agents, coloring agents, flavors, etc. Can do. Moreover, components such as bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents and the like can be blended as necessary.
The preparation technology for making the above-mentioned dosage form so as to include the drug of the present invention as the main component is known.

  When the compound or derivative (including salt) of the present invention is administered, its form is not particularly limited, and it may be administered orally or parenterally by a commonly used method. The dosage of the drug of the present invention can be appropriately determined finally based on the judgment of a doctor or veterinarian in consideration of the type of dosage form, administration method, patient age and weight, patient symptoms, and the like.

  In the drug of the present invention, the concentration of rifampicin or a derivative thereof is not particularly limited, but for example, 10 to 500 mg, preferably 50 to 200 mg, per 1 kg of the target organ (liver or liver cell) of the individual to be administered. More preferably, the density | concentration which becomes 50-100 mg can be illustrated.

  The organism to be administered with the drug of the present invention is usually a mammal, and examples thereof include organisms such as humans, dogs, and cats.

  It should be noted that all prior art documents cited in the present specification are incorporated herein by reference.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

[Example 1] Inhibitory effect of lung cancer (A549) metastasized to the liver in nude mice The effect of rifampicin on the proliferation of lung cancer cells (A549) transplanted into the liver via spleen in nude mice was examined.
As transplanted cells, 1.5 × 10 ⁶ cells / 50 μL / body of lung cancer cells (A549) were used. As anesthesia before transplantation, 5 mg / mL Nembutal was intraperitoneally administered at a volume of 10 μL / g body weight about 5 minutes before the transplantation procedure.

  The transplant site and transplant method are as follows. First, mice (mice, males, BALB / cA Jcl-nu nu / nu) were cut open in the dorsoventral axis direction by about 10 mm each in the skin and muscle layer of the left flank. Pull out the spleen from the abdominal cavity using round tweezers, pinch the lower end (ventral side) of the spleen, stab the needle approximately 3-5 mm from the end, and insert the needle tip into the spleen 5-7 mm Inserted and slowly infused the cell suspension. The cell suspension was filled in 50 μL in a 1 mL syringe equipped with a No. 27G needle. After injecting the cell suspension, the needle tip was held in the spleen for about 10 seconds, waited for the internal pressure to drop, the needle was removed, and the injection solution leaking from the scar was wiped off with Kimwipe. In order to prevent the organ from drying, the spleen was covered with absorbent cotton soaked in saline and squeezed firmly. Since anesthetized mice tend to drop in body temperature, they were placed on dry cotton wool to keep them warm and waited for 10 minutes for the transplanted cells to transfer to the liver.

  The spleen was removed and sutured as follows. Pass a suture (silk soft suture No. 3) between the pancreas using tweezers from the center of the spleen in advance and make a knot in each of the two blood vessels (dorsal and ventral) running through the spleen. During the minutes, ligation was performed from the ventral blood vessel, and then the dorsal blood vessel and a portion of the spleen were ligated together. While holding the thread ligating the ventral blood vessel with tweezers, the spleen was removed while pulling the spleen with ring tweezers, and the position where the knot of the thread was not removed was cut off with scissors. Excess suture was cut, the internal organs were returned to the abdominal cavity, and the muscle layer was sutured at one place with suture # 2. The skin was stapled and the blood stains were wiped back into the cage. Moreover, it kept warm with the hotplate etc. as needed, and the recovery | restoration from anesthesia and a postoperative was adapted.

Rifampicin (GK-001) is orally administered at doses of 50, 100 and 200 mg / kg once a day from the 4th day after cancer cell transplantation for 5 days a week (Saturday and Sunday is closed) for about 3 weeks. did.
5-FU was repeatedly administered at a dose of 30 mg / kg once a day from the 4th day after cancer cell transplantation for 5 days a week (saturday and Sunday with no drug) for about 3 weeks. The drug was suspended in 0.5 w / v% sodium carboxymethylcellulose solution (0.5% CMC-Na) and orally administered by gavage using a 1 mL syringe and a metal gastric sonde for mice. Only 0.5% CMC-Na was administered to the control group.

(A) General state observation The results of the general state observation are shown in Table 1 below. From the 16th to the 18th day of observation, skin whitening, decreased body temperature and decreased activity were observed in 5 cases in the control group, and 2 cases died immediately before blood sampling on the 18th day of observation. The above symptoms and cause of death in the control group were thought to be due to the rapid deterioration of the general condition due to metastatic liver cancer. On the other hand, in each administration group of rifampicin, no abnormality was observed until the 15th day of observation, but from the 16th to 18th day of observation, 1 case in the 50 mg / kg group and 2 cases in the 200 mg / kg group Yellowing, decreased body temperature and decreased activity were observed, and one patient at 200 mg / kg died on the 17th day of observation. In each rifampicin administration group, there was no clear effect to suppress the above-mentioned symptom expression and death due to metastatic liver cancer in a dose-dependent manner. This suggests the possibility of suppressing the deterioration of the general condition caused by metastatic liver cancer. In the 5-FU administration group, only redness of the skin was observed in one case from the 15th to the 18th observation, and no symptoms suggesting a sudden deterioration of the general condition due to metastatic liver cancer were observed throughout the observation period. Results supporting the progression of metastatic liver cancer were obtained.
The clinical signs on day 18 are shown in Table 1.

In the control group, some appearance abnormalities were observed in 5/7 cases, but no appearance abnormality was observed in the rifampicin 100 mg / kg group.
Further, Table 2 shows the pathological observation results regarding the degree of tumor (cancer) cell metastasis and vacuolation in the liver.

  In the table, “-” indicates no transition, “+”, “++”, and “+++” indicate that the degree of transition is weak, medium, and strong, respectively.

  Strong metastasis and proliferation were observed in all the control group. Rifampicin tended to suppress metastasis and proliferation, and hepatic parenchymal cells were vacuolated with metabolic enzyme induction in the rifampicin 100 and 200 mg / kg groups.

(B) Monitoring with cancer marker CA15-3 Further, monitoring with cancer marker CA15-3 was performed using CA15-3 ELISA kit (Panomics) as an assay kit.
Specifically, on the 18th day of observation (22 days after cancer cell transplantation), anesthesia was performed with ether, and as much blood as possible was collected from the abdomen of the vena cava using a heparin-coated syringe. The collected blood was immediately centrifuged at 1,870 × g for 10 minutes, and the obtained plasma was used for measurement. The measurement was performed as follows.

1) Plasma samples were diluted with an equal volume of dilution buffer (provided with ELISA kit), and each sample was dispensed into 2 wells of 100 microL and allowed to stand at room temperature (25 ° C.) for 5 hours.
2) Washed 5 times with 0.02% Tween20 / PBS.
3) 200 microL of HRP-labeled detection antibody (attached to ELISA kit) was added to each well and allowed to stand at 37 ° C. for 2 hours.
4) Washed 5 times with 0.02% Tween20 / PBS.
5) 100 microL of TMB was added to each well and allowed to stand at room temperature (25 ° C) until color was developed.
6) 100 microL of 1N HCl was added to each well to stop color development.
7) Absorbance was measured at 450 nm.

A graph in which the measured absorbance is converted into the plasma concentration of the cancer antigen is shown in FIG. Moreover, the total value for each administration group is shown in FIG. Although not shown for software reasons, a statistically significant difference was observed in the 100 mg group.
From the above results, in the group to which 100 mg of rifampicin was orally administered, a significant decrease in the cancer marker CA15-3 in the blood was observed, and clinical symptoms were significantly improved.

[Example 2] Inhibitory effects of orally administered rifampicin and its derivatives on the growth and metastasis of LL / 2 Lewis lung cancer cells in different animals Male nude mice BALB / C AnNCri-nu / nu were treated with LL / 2 cells (10 ⁶ cells / animal) was transplanted subcutaneously, and when the cancer size reached 200 mm ³ , drinking water containing 0.8 mg / mL rifampicin, 3-formylrifamycin SV, rifamycin SV was freely given. One group consisted of 7 mice. The size of the subcutaneous transplanted cancer was expressed in volume (FIG. 3-a). Evaluation of metastatic cancer to the liver and lung was expressed by taking a picture of each sliced organ and calculating the area of the cancer area (FIGS. 3-b and 3-c).

FIG. 1 is a graph in which the measured absorbance is converted into the plasma concentration of a cancer antigen. STD. 0.0-4.7 are standard samples of 0.0-4.7 U / mL, respectively. 1-7 is the control administration group. 8-14 in the 50 mg group. 15-21 is the 100 mg group. 22-27 was in the 200 mg group. 51-57 show 5-FU administration groups, respectively. FIG. 2 is a graph showing the relationship between rifampicin administration and plasma CA15-3 concentration. The plasma CA15-3 concentration in the rifampicin 100 mg / kg group was significantly lower (p <0.05) than that in the control group. FIG. 3-a is a graph showing a growth curve of subcutaneously transplanted cancer. White circles indicate non-cancer cell controls, black circles indicate controls, black squares indicate 3-formylrifamycin SV, black triangles indicate rifamycin SV, and black diamonds indicate rifampicin. FIG. 3-b is a graph showing the evaluation of metastatic cancer to the liver. FIG. 3-c is a graph showing the evaluation of metastatic cancer to the lung.

Claims (7)

  A therapeutic agent for liver cancer comprising rifampicin or a derivative thereof as an active ingredient.   The therapeutic agent according to claim 1, wherein the liver cancer is hepatocellular carcinoma.   The therapeutic agent according to claim 1, wherein the liver cancer is metastatic liver cancer.   The therapeutic agent according to claim 3, wherein the metastatic liver cancer is metastatic cancer from lung cancer, stomach cancer, rectal cancer, colon cancer, colon cancer, pancreatic cancer, or breast cancer.   A cancer metastasis inhibitor comprising rifampicin or a derivative thereof as an active ingredient.   The cancer metastasis inhibitor according to claim 5, wherein the cancer metastasis is cancer metastasis to the liver.   The cancer metastasis inhibitor of claim 6, wherein the cancer metastasis is lung cancer, gastric cancer, rectal cancer, colon cancer, colon cancer, pancreatic cancer, or breast cancer metastasis to the liver.