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Quinacrine hydrochloride

Quinacrine dihydrochloride is the dihydrochloride salt of the 9-aminoacridine derivative quinacrine with potential antineoplastic and antiparasitic activities. Quinacrine may inhibit the transcription and activity of both basal and inducible nuclear factor-kappaB (NF-kappaB), which may result in the induction of tumor suppressor p53 transcription, the restoration of p53-dependent apoptotic pathways, and tumor cell apoptosis. Continuous NF-kappaB signaling, present in many tumors and in chronic inflammatory processes, promotes the expression of antiapoptotic proteins and cytokines while downregulating the expression of proapoptotic proteins, such as p53. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus) .

Quinacrine (trade name Atabrine) is a drug with a number of different medical applications. It is related to mefloquine.

Medical application

(This section was directly from http://en.wikipedia.org/wiki/Quinacrine)

Its main effects are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent. Antiprotozoal use include targeting Giardiasis, where quinacrine is indicated as a primary agent for patients with metronidazole-resistant giardiasis and patients who should not receive or can not tolerate metronidazole. Giardiasis that is very resistant may even require a combination of quinacrine and metronidazole. Quinacrine is also used "off-label" for the treatment of systemic lupus erythematosus,  indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take chloroquine derivatives. As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients. Quinacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. View Mefloquine page for more information.

History of uses as medicine

(This section was directly from http://en.wikipedia.org/wiki/Quinacrine)

Antiprotozoal:  Quinacrine was initially approved in the 1930s as an antimalarial drug. This antiprotozoal is also approved for the treatment of Giardiasis (an intestinal parasite)[3], and has been researched as an inhibitor of phospholipase A2. Scientists at Bayer in Germany first synthesised Quinacrine in 1931 and subsequently marketed as Mepacrine or Atebrine. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.

Anthelmintics: In addition it has been used for treating tapeworm infections.

Creutzfeldt-Jakob disease: Quinacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro, and full clinical trials of its use as a treatment for Creutzfeldt-Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease, although other reports have shown no significant effect,  and treatment of scrapie in mice and sheep has also shown no effect.  Possible reasons for the lack of an in-vivo effect include inefficient penetration of the blood brain barrier, as well as the existence of drug-resistant prion proteins that increase in number when selected for by treatment with quinacrine.

Quinacrine non-surgical sterilization for women (QS): The use of quinacrine for non-surgical sterilization for women has also been researched. This method , was developed by Zipper et al. who reported a first year failure rate of 3.1%. However, despite a multitude clinical studies on the use of quinacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use. Pellets of quinacrine are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The procedure is undertaken twice, first in the proliferative phase, 6 to 12 days following the first day of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a six week interval to close off the tubes permanently.

Current developer:   

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2: Jani TS, DeVecchio J, Mazumdar T, Agyeman A, Houghton JA. Inhibition of NF-kappaB signaling by quinacrine is cytotoxic to human colon carcinoma cell lines and is synergistic in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or oxaliplatin. J Biol Chem. 2010 Jun 18;285(25):19162-72. Epub 2010 Apr 27. PubMed PMID: 20424169; PubMed Central PMCID: PMC2885195.

3: Wang Y, Bi Q, Dong L, Li X, Ge X, Zhang X, Fu J, Wu D, Li S. Quinacrine enhances cisplatin-induced cytotoxicity in four cancer cell lines. Chemotherapy. 2010;56(2):127-34. Epub 2010 Apr 20. PubMed PMID: 20407239.

4: Geng Y, Kohli L, Klocke BJ, Roth KA. Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent. Neuro Oncol. 2010 May;12(5):473-81. Epub 2010 Jan 27. PubMed PMID: 20406898.

5: Sokal DC, Vach TH, Nanda K, McCann MF, Weiner DH, Drobnes C, Rochanawutanon M, Duc NB, Loan ND. Quinacrine sterilization and gynecologic cancers: a case-control study in northern Vietnam. Epidemiology. 2010 Mar;21(2):164-71. PubMed PMID: 20160560.

6: McConnell EE, Lippes J, Growe RG, Fail P, Luster MI, Zeiger E. An alternative interpretation of, "A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats". Regul Toxicol Pharmacol. 2010 Mar;56(2):166-73. Epub 2010 Jan 4. PubMed PMID: 20043971.

7: Sokal DC, Trujillo V, Guzmán SC, Guzman-Serani R, Wheeless A, Hubacher D. Cancer risk after sterilization with transcervical quinacrine: updated findings from a Chilean cohort. Contraception. 2010 Jan;81(1):75-8. Epub . PubMed PMID: 20004277.

8: Gurova K. New hopes from old drugs: revisiting DNA-binding small molecules as anticancer agents. Future Oncol. 2009 Dec;5(10):1685-704. Review. PubMed PMID: 20001804; PubMed Central PMCID: PMC2821823.

9: Chau CH, Figg WD. New tricks from an old drug: a role for quinacrine in anti-cancer therapy? Cell Cycle. 2009 Dec 15;8(24):4024-5. Epub 2009 Dec 15. PubMed PMID: 19959937.

10: Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, DeArmond SJ, Prusiner SB. Continuous quinacrine treatment results in the formation of drug-resistant prions. PLoS Pathog. 2009 Nov;5(11):e1000673. Epub 2009 Nov 26. PubMed PMID: 19956709; PubMed Central PMCID: PMC2777304.

11: Neznanov N, Gorbachev AV, Neznanova L, Komarov AP, Gurova KV, Gasparian AV, Banerjee AK, Almasan A, Fairchild RL, Gudkov AV. Anti-malaria drug blocks proteotoxic stress response: anti-cancer implications. Cell Cycle. 2009 Dec;8(23):3960-70. Epub 2009 Dec 25. PubMed PMID: 19901558.

12: Cancel AM, Dillberger JE, Kelly CM, Bolte HF, Creasy DM, Sokal DC. A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats. Regul Toxicol Pharmacol. 2010 Mar;56(2):156-65. Epub 2009 Jul 23. PubMed PMID: 19631709.

13: Wong IL, Chan KF, Zhao Y, Chan TH, Chow LM. Quinacrine and a novel apigenin dimer can synergistically increase the pentamidine susceptibility of the protozoan parasite Leishmania. J Antimicrob Chemother. 2009 Jun;63(6):1179-90. Epub 2009 Apr 17. PubMed PMID: 19377065.

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