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WO2010003232A1 - Traitement du cancer à l’aide d’atractyloside - Google Patents

Traitement du cancer à l’aide d’atractyloside Download PDF

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Publication number
WO2010003232A1
WO2010003232A1 PCT/CA2009/000937 CA2009000937W WO2010003232A1 WO 2010003232 A1 WO2010003232 A1 WO 2010003232A1 CA 2009000937 W CA2009000937 W CA 2009000937W WO 2010003232 A1 WO2010003232 A1 WO 2010003232A1
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Prior art keywords
cancer
atr
effective amount
therapeutically effective
pharmaceutically acceptable
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PCT/CA2009/000937
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English (en)
Inventor
Vladimir Pak
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Constab Pharmaceutical Inc
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Constab Pharmaceutical Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to uses of atractyloside (ATR), carboxyatractyloside (CATR), and ATR- and CATR-containing compositions for treating cancers, and compositions containing the same.
  • ATR atractyloside
  • CATR carboxyatractyloside
  • ATR- and CATR-containing compositions for treating cancers, and compositions containing the same.
  • cytotoxic agents that act directly on the mitochondria such as lonidamine, arsenite, betulinic acid and CD437 has provided an alternative therapeutic strategy in circumstances where conventional drugs fail due to disruption of endogenous apoptosis induction pathways, such as those involving ⁇ 53 (Costantini et al, J. Natl. Cancer Institute 92: 1042-1053, 2000). Costantini et al. reviews the mechanism of inducing apoptosis through mitochondrial destruction by alteration of mitochondrial membrane permeability and/or changes in the permeability transition pore complex (PTPC) (Costantini et al., J. Natl. Cancer Inst. 92(13): 1042-53, 2000).
  • PTPC permeability transition pore complex
  • Agents identified as being capable of damaging the mitochondria have varying toxicity profiles. Less toxic examples include betulinic acid (BA), which has been used to t.-eat melanoma (U.S. Patent Application Publication No. 2003/0186945). More toxic agents targeting the mitochondria include atractyloside (ATR) and carboxyatractyloside (CATR), as well as rotenone, piercidine A, and bongkrekic acid (BKA), for example (Rex, M.C. et al., Data for biochemical research, Oxford Science Publications, Claredon Press, Oxford, Third Edition, p.297, 1986).
  • BA betulinic acid
  • CAR carboxyatractyloside
  • BKA bongkrekic acid
  • ATR is a naturally occurring diterpenoid glycoside found in many plants including Atractylis gummifera (from which it was first extracted from rhizomes) and Callilepsis laureola, where it exists primarily in the root tubers. In South Africa, the tuberous rootstock of Callilepsis laureola is used to prepare "Impila", the Zulu word for "health”. Impila is used as a traditional herbal remedy in many African countries to treat a number of different ailments including body toxicity; anxiety; bacterial and viral diseases including tuberculosis, measles, pneumonia, and gastro-intestinal problems; whooping cough; tape-worm infestation; and impotence.
  • Impila is also used to induce fertility (Debetto, in "Atractyloside: Chemistry, Biochemistry and Toxicology", eds. R. Santi & S. Luciani, pp. 125-129, 1978) and to faciliate labour (Veale et al., J. Ethnopharm. 36:185- 191, 1992).
  • the roots of Atractylis gummifera have also been ground into a powder and used to treat glandular tumors (Hartwell J.L., Plants used against cancer, Quarterman Publications, Inc., p.l 19, 1982).
  • Impila extract results in the extraction namely of ATR and carboxyatractyloside (CATR), the latter of which is unstable and thermally decomposes to ATR (Bombardelli, Phytochemistry 11 :3501-4, 1972).
  • CACR carboxyatractyloside
  • Impila has also been shown to correlate with severe hepato- and nephrotoxicity (Stewart MJ. and Steenkamp V. (2000) Ther. Drug Monitoring 22(6):641-649).
  • studies have shown that the highly toxic effects of Impila are not due to ATR alone.
  • Impila While administration of Impila or ATR individually gives rise to disruption of mitochondrial membranes, destruction of the tubulin network, and inhibition of cell division, Impila has been shown to induce hepatic and renal necrosis whereas purified ATR does not induce similar hepatotoxicity (Popat et al., Clin. Biochem. 35:57-64, 2002).
  • a number of studies of ATR toxicity have been conducted in a variety of species. Table 1 summarizes studies of ATR toxicity in different species including mice, rat, guinea pig, rabbit, and dog. While acute toxicity has been well described, subchronic and chronic toxicity, reproductive toxicity, mutagenicity and carcinogenicity have not been investigated (Obatomi et al., Toxicol. Appl. Pharmacol. 148(l):35-45, 1998; and Obatomi D.K. et al. (1998) Toxicol. Appl. Pharmacol, 148(l):35-45).
  • ATR cytosolic side-specific mitochondrial ADP/ATP carrier
  • ATR acts as a permeability transition pore-opening agent, capable of inducing apoptosis upon microinjection into cells (Marzo et al., Science 281 :2027-2031, 1998).
  • ATR The biochemistry of ATR is well known.
  • ATR consists of two biologically active parts: an aglycone and a glycoside moiety (Obatomi and Bach, Food Chem. Toxicol. 36:335-346, 1998).
  • the structural integrity of ATR has been shown to be integral to the biological effects of ATR, as the aglycone (atractyligenin) is 150-fold less potent at inhibiting oxidative phosphorylation in mitochondria compared to the glycoside.
  • atractyligenin derivatives were synthesized and added to the culture medium of K- 562, HL-60 and MCF-7 cells.
  • IC50 values were calculated and it was determined that the most toxic atractyligenin derivative had an IC 50 value in the range of 0.8-6.9 ⁇ M.
  • One of the atractyligenin derivatives tested was shown to have an EC 50 in the range of 0.2 ⁇ M-0.3 ⁇ M when tested in the IA9 ovarian cancer cell line (Rosselli S. et al. (2007) J. Nat. Prod. 70:347-352).
  • Esperamicin Al injected intravenously at a dose of 1.25 ⁇ g/kg was shown to suppress P- 388 tumor cell growth by up to 85% in vivo in a murine model. Mice administered Esperamicin Al demonstrated an increase in survival up to 26% compared to control animals (Severin, S.E. et al. (1999) Dokl. Akad. Nauk. 366(4):561-4).
  • cancer cells and normal cells absorb oil-based and water-based drug formulations with different efficiency. Cancer cells have been shown to be capable of absorbing liposomes with greater efficiency than normal cells (Le Bang, S. et al. (2002) “Research of cytotoxic activity of betulinic acid, its derivatives and liposome form in vitro", Voprosi Biologicheskoi, Medicinskoi i Pharmacevticheskoi Khimii, n. 4, p. 31-34). This finding suggests that liposome-based drug delivery is ideal for targeting tumour cells as it has reduced side effects on normal cells. Previously, it was demonstrated that the nephrotoxic side effects of the anticancer drug cisplatinum can be reduced when delivered via liposomes (Boulikas, T. (2004) Oncology Reports 12:3-13).
  • a pharmaceutical composition for treating cancer comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • a pharmaceutically acceptable carrier in the preparation of a medicament for treating cancer is provided.
  • composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier, for treating multidrug resistance in a refractory malignant neoplasm is provided.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • a method of inhibiting cancer cell proliferation in a mammal comprises administering to a mammal a therapeutically effective amount of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • a method for treating multidrug resistance in refractory malignant neoplasms comprising administering to a mammal a therapeutically effective amount of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • FIG. 1A is a schematic of the chemical structure of Atractyloside (ATR).
  • FIG. 1B is a schematic of the chemical structure of Carboxyatractyloside (CATR).
  • CAR Carboxyatractyloside
  • Figure 2 is a graph of data from experiments investigating the inhibition of 10 6 breast adenocarcinoma Ca-755 cells inoculated subcutaneously into BDFi female mice.
  • Test mice were treated with an oil suspension of ATR at a dose of 0.1 mg/kg, as 0.2 ml in their feed beginning day one post-inoculation (circles).
  • Control mice were treated with 0.2 ml of oil alone (triangles, hatched line) or water (squares). All treatments were carried out for 25 days.
  • Figure 3 is a graph of data from the same experiments described in Figure 2 plotting survival time (%) against days post inoculation. In this graph, the oil control is represented by diamond symbols.
  • the present invention relates to the use of ATR and CATR for treating cancer.
  • ATR has been shown to induce apoptosis in HuH-7 cells that lack normal p53 function suggesting that ATR may induce apoptosis via a p53-independent pathway (Stewart et al. (2002) Hum. Exper. Toxicol. 21 :643-647). Given that deregulation of 53 activities has been identified as a cause of MDR, the data suggest that ATR can possibly overcome multiple drug resistance in certain cancers and induce cancer cell apoptosis. ATR has also been shown to inhibit tubulin assembly in addition to its effects on mitochondria, similar to the anti-cancer agent paclitaxel (Stewart and Steenkamp (2000) Ther. Drug Monitoring 22(6):641-649). Thus, ATR was investigated as an anti-cancer agent.
  • a pharmaceutical composition for treating cancer comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • the invention provides for the use of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier, in the preparation of a medicament for treating cancer.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • the invention provides for the use of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier, for treating multidrug resistance in a refractory malignant neoplasm.
  • a method of inhibiting cancer cell proliferation in a mammal comprising administering to a mammal a therapeutically effective amount of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • a method for treating multidrug resistance in refractory malignant neoplasms comprising administering to a mammal a therapeutically effective amount of a composition comprising a therapeutically effective amount of a compound selected from the group consisting of atractyloside (ATR) and carboxyatractyloside (CATR); and a pharmaceutically acceptable carrier.
  • ATR atractyloside
  • CAR carboxyatractyloside
  • oil refers to edible liquid oils, including fish oils, vegetable oils, sunflower oil, flaxseed oil, etc.
  • the ATR compositions disclosed herein are useful in the treatment of a variety of cancers including but not limited to melanoma, breast cancer, stomach cancer, bladder cancer, liver cancer, pancreatic cancer, colon cancer, sarcoma, prostate cancer, lung cancer, glioma, nueroblastoma and glandular tumours.
  • ATR compositions can be administered to a subject by any suitable route, for example by any one of oral; buccal; sublingual; inhalation; rectal; topical; or intravenous, intramuscular, cutaneous or subcutaneous injection.
  • the formulation of the composition will depend on the route of administration.
  • the formulation is preferably a tablet, capsule, powder, or solution. If liquid form, a liquid carrier such as water or oil can be added.
  • the formulation is preferably an aqueous solution.
  • the formulation is preferably an aerosol spray.
  • the formulation is preferably suspension. More preferably, the suspension is an oil suspension.
  • the formulation is preferably a suppository or retention enema.
  • the composition can be a liposomal formulation or a nanoparticle formulation.
  • BDFi female mice were inoculated subcutaneously with IXlO 6 Ca-755 breast adenocarcinoma cells suspended in 0.3 mL of RPMI- 1640 culture medium.
  • Cells were initially resected from established cell line inoculation in the murine Black/6 strain. Briefly, tumours were resected from Black/6 mice and washed in RPMI- 1640 culture medium. Tumour tissue was minced in order to obtain a single cell suspension. Cells were then cultured in RPMI- 1640 culture medium at a ratio of 14 mL culture medium per 1 g of tumour tissue providing a 1:15 dilution of tumour to culture medium.
  • the dose of ATR was calculated based on a typical human herbal remedy dosage.
  • the amount of ATR extracted from Callilepsis laureola root tuber is 6.7 ⁇ g/g of root.
  • 1O g of raw plant material contains an average of 67 ⁇ g ATR. It was previously demonstrated that this dosage of Impila, taken orally over a period of time, contained sufficient toxin to cause severe kidney damage (Obatomi D.K. and Bach P.H. (1998) Food Chem. Toxicology 36:335-346).
  • the coefficient of 104 used in formula 2) is taken from Boik ("Natural Compounds in Cancer Therapy: Promising Nontoxic Antitumor Agents from Plants & Other Animal Sources", Oregon Medical Press, Minnesota, 2001), and is used for the conversion of human dose into equivalent murine dose.
  • the therapeutically effective amount of ATR can be in the range of about 0.01 - 100 mg/kg for mice or about 0.1 ⁇ g/kg - 1 mg/kg for human (about 7.5 ⁇ g - 75 mg unit dose for a human weighing 75 kg), with a preferred dosage range being from about 1 ⁇ g/kg - 500 ⁇ g/kg (unit dose of about 75 ⁇ g to 37.5 mg), most preferably from about 10 ⁇ g/kg to 100 ⁇ g/kg (unit dose of about 0.75 mg to 7.5 mg).
  • ATR and CATR have been shown to be effective at inhibiting tumour cell proliferation in the range of 10-100 ⁇ M (D'Ancona et al. (1989) Fitorick 60(6):509- 516). Further more, acute toxicity of ATR has been shown to differ in each of a species- dependent and route of administration-dependent manner (Luciani and Carpenedo, in "Atractyloside: Chemistry, Biochemistry and Toxicology", eds. R. Santi & S. Luciani, pp. 109-124, 1978). Given the nephrotoxicity associated with ATR, oil suspensions containing ATR were prepared for treating mice inoculated with Ca-755 tumour cells.
  • ATR was prepared as an oil suspension for oral gavage treatment of mice in a breast carcinoma model. 1 mg of ATR powder (Sigma) was dissolved in 100 ml of vegetable oil by rigorous mixing until ATR particles were no longer visible. Mice were administered a daily dose of 0.2 ml of this preparation, containing 2 ⁇ g of ATR (or 0.1 mg/kg per day). Preparation of ATR in the oil is believed to enhance absorption of the drug compared to water-based solutions.
  • BDF 1 female mice were injected subcutaneously with IXlO 6 Ca-755 breast adenocarcinoma cells suspended in 0.3 mL of RPMI- 1640 culture medium.
  • ATR was administered to mice in a daily dose of ATR in oil suspension (0.1 mg/kg) starting at day one post-tumour cell inoculation.
  • the dose of ATR was converted from typical human dose according to Boik (in "Natural Compounds in Cancer Therapy: Promising Nontoxic Antitumor Agents from Plants & Other Animal Sources", Oregon Medical Press, Minnesota, 2001).
  • mice were fed by oral gavage with the oil suspension of ATR. Due to the natural way in which lipids digest, the ATR oil formulation is emulsified in the intestinal tract by bile acids and, as in the case of fat-soluble vitamins, ATR absorption is believed to be promoted by the oil. It is anticipated that the absorption of this emulsion into the bloodstream may exhibit similar beneficial properties as have been demonstrated with liposomal formulations that are injected by the iv route, as discussed above.
  • mice [0050] Three groups of 10 mice each were evaluated:
  • Group 1 control mice were fed 0.2 mL of oil daily; Group 2 control mice were fed 0.2 mL water; and
  • mice were fed 0.2 mL of oil suspension containing 2 ⁇ g of ATR daily (0.1 mg/kg);
  • Group 1 and 3 animals were fed by oral gavage preparations. All treatment regimens were initiated day one post-inoculation of tumour cells. The duration of the treatment was 25 days. All animals were carefully monitored for signs of toxicity including weight loss. No weight loss was detected in any group suggesting ATR treatment was not associated with any toxic side effects, such as nephrotoxicity.

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  • Medicinal Chemistry (AREA)
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Abstract

La présente invention concerne une composition d’atractyloside (ATR) ou de carboxyatractyloside (CATR) destinée au traitement du cancer. Il est montré que le traitement de tumeurs à l’aide d’ATR réprime la croissance tumorale et amplifie les temps médians de survie dans un modèle de cancer du sein. Il est également montré que des compositions d’ATR sont utiles dans le traitement de tumeurs réfractaires à d’autres protocoles chimiothérapeutiques.
PCT/CA2009/000937 2008-07-07 2009-07-06 Traitement du cancer à l’aide d’atractyloside Ceased WO2010003232A1 (fr)

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US12959108P 2008-07-07 2008-07-07
US61/129,591 2008-07-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112022864A (zh) * 2020-09-16 2020-12-04 深圳市龙华区中心医院 苍术苷在制备治疗脂肪肝的药物中应用
CN113274420A (zh) * 2021-04-27 2021-08-20 苏州科技大学 一种靶向筛选茅苍术抗乳腺癌活性成分的方法
CN114469967A (zh) * 2021-12-20 2022-05-13 江西中医药大学 一种苍术苷a及其衍生物在制备抗焦虑和抗抑郁药物上的应用
CN115607676A (zh) * 2022-10-19 2023-01-17 中山大学附属第八医院（深圳福田） 羧基苍术苷在制备抗肿瘤耐药性的药物中的应用

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CN2587415Y (zh) * 2002-07-04 2003-11-26 马旭 抗肿瘤药丸
WO2007056852A1 (fr) * 2005-11-15 2007-05-24 Constab Pharmaceutical, Inc. Compositions d'alphafoetoproteine et d'inducteurs d'apoptose pour le traitement du cancer

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CN2587415Y (zh) * 2002-07-04 2003-11-26 马旭 抗肿瘤药丸
WO2007056852A1 (fr) * 2005-11-15 2007-05-24 Constab Pharmaceutical, Inc. Compositions d'alphafoetoproteine et d'inducteurs d'apoptose pour le traitement du cancer

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PAK V.: "The Use of AFP-Complexes to Induce Apoptosis in Cancer Cells.", THE OPEN CANCER JOURNAL, vol. 2, 20 May 2008 (2008-05-20), pages 12 - 14, ISSN: 1874-0790, Retrieved from the Internet <URL:http://bentham.org/open/tocj/openaccess2.htmD4> *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112022864A (zh) * 2020-09-16 2020-12-04 深圳市龙华区中心医院 苍术苷在制备治疗脂肪肝的药物中应用
CN113274420A (zh) * 2021-04-27 2021-08-20 苏州科技大学 一种靶向筛选茅苍术抗乳腺癌活性成分的方法
CN114469967A (zh) * 2021-12-20 2022-05-13 江西中医药大学 一种苍术苷a及其衍生物在制备抗焦虑和抗抑郁药物上的应用
CN114469967B (zh) * 2021-12-20 2024-02-20 江西中医药大学 一种苍术苷a及其衍生物在制备抗焦虑和抗抑郁药物上的应用
CN115607676A (zh) * 2022-10-19 2023-01-17 中山大学附属第八医院（深圳福田） 羧基苍术苷在制备抗肿瘤耐药性的药物中的应用
CN115607676B (zh) * 2022-10-19 2024-03-01 中山大学附属第八医院（深圳福田） 羧基苍术苷在制备抗肿瘤耐药性的药物中的应用

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