Application of nicotinic acid and derivatives thereof in preventing or treating growth and metastasis of colorectal cancer
By developing nicotinic acid derivatives, the problems of drug resistance and distant metastasis in the treatment of colorectal cancer, especially liver metastasis, have been solved, achieving significant effects in inhibiting and preventing the metastasis of colorectal cancer cells, and providing a new drug treatment option.
Patent Information
- Application Number
- CN202512027305.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-30
- Publication Date
- 2026-03-20
AI Technical Summary
Current technologies for treating colorectal cancer suffer from problems such as drug resistance, recurrence, and distant metastasis, especially liver metastasis, and there is a lack of effective therapeutic targets and drugs.
To develop a nicotinic acid derivative that inhibits the proliferation, migration, and invasion of colorectal cancer cells and significantly inhibits liver metastasis in a mouse model, and to prepare a safe and effective drug in combination with other drugs.
Nicotinic acid derivatives significantly inhibit the growth and metastasis of colorectal cancer cells, especially liver metastases, providing a new drug approach for the treatment of colorectal cancer, with both safety and efficacy.
Smart Images
Figure CN121698936A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of biomedicine, specifically relating to a nicotinic acid derivative and its applications. Background Technology
[0002] Colorectal cancer is one of the most common malignant tumors of the digestive system. It ranks third in incidence among all malignant tumors and is the second leading cause of cancer death, after lung cancer. Although surgical resection, radiotherapy, chemotherapy, targeted therapy, and immunotherapy have improved patient prognosis to some extent, most patients still face the risks of drug resistance, recurrence, and distant metastasis during treatment, with liver metastasis being the most common and directly determining overall patient survival. Therefore, finding new therapeutic targets and developing new therapeutic drugs is crucial.
[0003] Niacin is an important component of vitamin B3, and together with nicotinamide, it participates in the synthesis of NAD⁺ / NADP⁺, playing a crucial role in cellular redox reactions and energy conversion. Niacin participates in maintaining genome stability, regulating mitochondrial function, and is involved in immune system regulation and neurotransmitter metabolism. Clinically, niacin is often used to treat pellagra and plays an important role in lowering blood lipids. Furthermore, current research suggests that niacin can help maintain normal epigenetic modifications by regulating deacetylases through NAD⁺ synthesis. However, research on the relationship between niacin and epigenetics is still relatively limited, and further experimental and clinical research is needed to understand and apply the role of niacin in epigenetics. Summary of the Invention
[0004] To address the above problems, the present invention provides a nicotinic acid derivative, the derivative having the following structural formula: .
[0005] The present invention also provides the use of the above-mentioned derivatives in the preparation of drugs for the prevention or treatment of colorectal cancer.
[0006] Furthermore, colorectal cancer includes both in situ growth and metastasis of colorectal cancer.
[0007] Furthermore, the metastases include lymph node metastases, lung metastases, liver metastases, bone metastases, and brain metastases.
[0008] The present invention has the following beneficial effects:
[0009] This invention is the first to discover that nicotinic acid and its novel derivatives can effectively and significantly inhibit the proliferation, migration, and invasion of colorectal cancer cells, and can also inhibit the growth and liver metastasis of colorectal cancer cells in a mouse model. Experiments have confirmed that the pharmaceutical reagents prepared using nicotinic acid or in combination with other drugs are safe and effective, providing a new approach for preparing drugs for the prevention or treatment of liver cancer. Attached Figure Description
[0010] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.
[0011] Figure 1 A schematic diagram showing the effect of niacin (NA) treatment on the proliferation ability of colorectal cancer MC38 cells;
[0012] Figure 2 This is a schematic diagram illustrating the effect of niacin (NA) treatment on the proliferation of colorectal cancer MC38 cells by acting on tumor-associated macrophages.
[0013] Figure 3 This is a schematic diagram showing the effect of niacin (NA) treatment on subcutaneous tumorigenesis of colorectal cancer in mice.
[0014] Figure 4 A schematic diagram showing the effect of niacin (NA) treatment on the migration and invasion abilities of colorectal cancer MC38 cells;
[0015] Figure 5 This is a schematic diagram illustrating the effect of niacin (NA) treatment on the migration and invasion abilities of colorectal cancer MC38 cells by acting on tumor-associated macrophages.
[0016] Figure 6 A schematic diagram showing the effect of niacin (NA) treatment on colorectal cancer liver metastasis in mice.
[0017] Figure 7 A schematic diagram showing the effect of niacin (NA) treatment on tumor-associated macrophage infiltration in colorectal cancer liver metastases in mice;
[0018] Figure 8 A schematic diagram showing the effects of treatment with physiological saline (NS), nicotinic acid (NA), or nicotinamide (NAM) on the levels of nicotinic acid-co-enzyme in the liver and kidneys of mice. Detailed Implementation
[0019] Various exemplary embodiments of the present invention are now described in detail. Unless otherwise specified, the methods used in the embodiments are conventional methods, and the reagents used are commercially available reagents or reagents prepared using conventional methods. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, characteristics, and embodiments of the present invention.
[0020] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.
[0021] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.
[0022] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.
[0023] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.
[0024] Example 1
[0025] This embodiment uses colorectal cancer cell line MC38 as an example to investigate the effect of niacin on the proliferation ability of MC38 cells. The specific steps are as follows:
[0026] After digestion and counting, MC38 cells were added to equal volumes in 96-well culture plates, seeded according to the number of days of detection, with 6 replicates per counting point. From the day of seeding, the treatment group received 20 mM nicotinic acid, while the control group received the corresponding buffer solution. Cells were cultured at 37°C in a 5% CO2 incubator, with CCK-8 reagent added to the corresponding wells at a fixed time each day. After culturing for another 2 hours in a constant temperature incubator, the OD450 value was measured.
[0027] After digestion and counting of MC38 cells, equal volumes of cells were added to 6-well culture plates. The treatment group received 20 mM nicotinic acid, while the control group received the corresponding buffer solution. After 48 hours of treatment, EdU was added to the cell supernatant. Cells were then cultured in an incubator for another 2 hours before flow cytometry analysis.
[0028] like Figure 1 As shown, nicotinic acid treatment significantly inhibited the proliferation of colorectal cancer cells MC38.
[0029] Example 2
[0030] In this embodiment, colorectal cancer cells MC38 and macrophages RAW264.7 were used as examples to investigate the effect of niacin on the proliferation of MC38 cells by acting on tumor-associated macrophages. The specific steps were as follows: MC38 cells were cultured in 1% FBS cell culture medium. After 48 hours, the supernatant of the MC38 cells was collected as MC38 cell conditioned medium (CM). RAW264.7 macrophages were treated with MC38 CM. The treatment group received 20 mM niacin, while the control group received the corresponding buffer solution. After 48 hours, the culture medium was replaced with 1% FBS cell culture medium, and RAW264.7 macrophages were cultured for another 24 hours. The supernatant was collected as RAW264.7 cell conditioned medium (RCM).
[0031] After digestion and counting, equal amounts of MC38 cells were added to 6-well culture plates. MC38 cells were cultured with RCM from both the treatment group and the control group. After 48 hours, EdU was added to the cell supernatant. The cells were then cultured in an incubator for another 2 hours before flow cytometry analysis.
[0032] After digestion and counting, MC38 cells were added to equal volumes in 96-well culture plates, seeding the cells according to the number of wells corresponding to the detection days, with 6 replicates per counting point. From the day of seeding, MC38 cells were cultured with RCM from both the treatment group and the control group, with CCK-8 reagent added to the corresponding wells at a fixed time each day. After culturing the cells in an incubator for 2 hours, the OD450 value was measured.
[0033] like Figure 2 As shown, nicotinic acid treatment significantly inhibited the ability of tumor-associated macrophages RAW264.7 to promote the proliferation of colorectal cancer cells MC38.
[0034] Example 3
[0035] This study investigated the effect of niacin (NA) on the growth of colorectal cancer in mice by conducting a subcutaneous tumor-bearing experiment. The specific steps were as follows: 4-5 week old male C57 / BL6J mice were subcutaneously inoculated with MC38 colorectal cancer cells, with 3 × 10⁵ cells per mouse. Four days after inoculation, the mice were randomly divided into two groups, and intratumoral administration of NA was initiated. The treatment group received 50 mg / ml NA, while the control group received physiological saline. Administration was repeated every 2-3 days, and tumor size was recorded. Twenty-one days after inoculation, the mice were euthanized by cervical dislocation, and samples were collected, weighed, and photographed.
[0036] like Figure 3As shown, nicotinic acid treatment significantly inhibited the growth of colorectal cancer in mice.
[0037] Example 4
[0038] This embodiment uses colorectal cancer cell line MC38 as an example to investigate the effect of niacin on the migration and invasion abilities of MC38 cells. The specific steps are as follows:
[0039] MC38 cells were treated with 20 mM nicotinic acid and corresponding buffer solutions, respectively. After 48 hours, the treated and control MC38 cells were digested and counted. Cell migration and invasion experiments were performed using Transwell chambers. Cell culture medium containing 20% FBS was added to the 24-well culture plate provided with the chamber, and cell suspension containing 0.5% FBS was added to the chamber. For invasion experiments, matrix gel diluted with culture medium was added to the chamber first. The chambers were placed in a cell culture incubator for incubation. After 24-48 hours, the Transwell chambers were collected, fixed with 4% paraformaldehyde, washed, and then crystal violet dye was added. The chambers were rinsed with water, observed, photographed, and counted.
[0040] like Figure 4 As shown, nicotinic acid treatment significantly inhibited the migration and invasion of MC38 colorectal cancer cells.
[0041] Example 5
[0042] This embodiment uses colorectal cancer cells MC38 and macrophages RAW264.7 as examples to investigate the effect of niacin on the migration and invasion ability of MC38 cells by acting on tumor-associated macrophages. MC38 cells were cultured with RCM from the niacin-treated group and the control group, respectively. After 48 hours, the MC38 cells in both groups were digested and counted. Cell migration and invasion experiments were performed using Transwell chambers. Cell culture medium containing 20% FBS was added to the 24-well culture plate of the chamber, and cell suspension containing 0.5% FBS was added to the chamber. For invasion experiments, matrix gel diluted with culture medium was added to the chamber first. The chambers were placed in a cell culture incubator for culture. After 24-48 hours, the Transwell chambers were collected, fixed with 4% paraformaldehyde, washed, and then crystal violet dye was added. The chambers were rinsed with water, observed, photographed, and counted.
[0043] like Figure 5 As shown, nicotinic acid treatment significantly inhibited the ability of tumor-associated macrophages RAW264.7 to promote the migration and invasion of colorectal cancer cells MC38.
[0044] Example 6
[0045] This embodiment investigates the effect of niacin (NA) on liver metastasis of colorectal cancer in mice, and a mouse tumor-bearing experiment was conducted. The specific steps were as follows: 4-week-old C57 / BL6J male mice were inoculated with MC38 colorectal cancer cells, with 4 × 10⁵ cells per mouse. Two days after inoculation, the mice were randomly divided into three groups, each group receiving physiological saline, 600 mg / kg niacin, or 600 mg / kg niacinamide via gavage, respectively, every 2–3 days. Twenty days after inoculation, the mice were sacrificed by cervical dislocation, and samples were collected, weighed, and photographed.
[0046] like Figure 6 As shown, nicotinic acid treatment significantly inhibited liver metastasis of colorectal cancer in mice.
[0047] Example 7
[0048] This example investigated the effect of niacin (NA) on tumor-associated macrophage infiltration in colorectal cancer liver metastases in mice. Liver tissue from the mice in Example 6 was analyzed by flow cytometry and tissue immunofluorescence. Figure 7 As shown, nicotinic acid treatment significantly inhibited the infiltration of tumor-associated macrophages in colorectal cancer liver metastases in mice.
[0049] Example 8
[0050] This embodiment provides a novel nicotinic acid derivative structure, wherein the derivative is a downstream metabolite of nicotinic acid, and the structural formula is as follows:
[0051]
[0052] Example 9
[0053] Male C57 / BL6J rats were administered physiological saline, 600 mg / kg nicotinic acid, or nicotinamide via gavage for 10 consecutive days. The rats were then sacrificed by cervical dislocation, and their tissues were collected. 10 mg of kidney or liver tissue was extracted and added to a cold extraction solution (10% (w / v) TCA). After sonication, the supernatant was collected. The supernatant was loaded onto an Oasis HLB-SPE column. After washing the column with ultrapure water, CoA compounds were eluted with a methanol solution containing 25 mM ammonium acetate. The samples were dried under nitrogen and analyzed.
[0054] like Figure 8 As shown, orally ingested niacin can be converted into the downstream metabolite nicotinic acid-CoA in the kidneys and liver of mice, while nicotinamide cannot.
[0055] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.
Claims
1. A nicotinic acid derivative, characterized in that, The derivative has the following structural formula: .
2. The use of the derivative as described in claim 1 in the preparation of a drug for the prevention or treatment of colorectal cancer.
3. The application according to claim 2, characterized in that, The colorectal cancer mentioned includes both in situ growth and metastasis of colorectal cancer.
4. The application according to claim 3, characterized in that, The metastases include lymph node metastases, lung metastases, liver metastases, bone metastases, and brain metastases.