Gallium maltolate explained

Gallium maltolate is a coordination complex consisting of a trivalent gallium cation coordinated to three maltolate ligands. The compound is a potential therapeutic agent for cancer, infectious disease, and inflammatory disease.[1] [2] [3] [4] A cosmetic skin cream containing gallium maltolate is marketed under the name Gallixa. It is a colorless solid with significant solubility in both water and lipids (octanol-water partition coefficient = 0.41).[1]

Mechanism of action

Gallium maltolate delivers gallium with higher oral bioavailability than that of gallium salts such as gallium nitrate and gallium trichloride.[1] In vitro studies have found gallium to be antiproliferative due primarily to its ability to mimic ferric iron (Fe3+). Ferric iron is essential for DNA synthesis, as it is present in the active site of the enzyme ribonucleotide reductase, which catalyzes the conversion of ribonucleotides to the deoxyribonucleotides required for DNA. Gallium is taken up by the rapidly proliferating cells, but it is not functional for DNA synthesis, so the cells cannot reproduce and they ultimately die by apoptosis. Normally reproducing cells take up little gallium (as is known from gallium scans), and gallium is not incorporated into hemoglobin, accounting for the relatively low toxicity of gallium.[5]

Research

Gallium (III) ion shows anti-inflammatory activity in animal models of inflammatory disease.[2] [5] Orally administered gallium maltolate has demonstrated efficacy against two types of induced inflammatory arthritis in rats.[6] Experimental evidence suggests that the anti-inflammatory activity of gallium may be due, at least in part, to down-regulation of pro-inflammatory T-cells and inhibition of inflammatory cytokine secretion by macrophages.[2] [5] [6] Because many iron compounds are pro-inflammatory, the ability of gallium to act as a non-functional iron mimic may contribute to its anti-inflammatory activity.[2]

Gallium maltolate has also been proposed for the treatment for primary liver cancer (hepatocellular carcinoma; HCC). In vitro experiments demonstrated efficacy against HCC cell lines,[4] and encouraging clinical results have been reported.[7]

Gallium compounds are active against infection-related biofilms, particularly those caused by Pseudomonas aeruginosa.[8] [9] In related research, locally administered gallium maltolate has shown efficacy against P. aeruginosa in a mouse burn/infection model.[10] The potential of this approach may be somewhat limited by the relatively rapid appearance of gallium-resistant isolates.[11] [12]

Oral gallium maltolate has been investigated as a treatment for Rhodococcus equi foal pneumonia, a common and often fatal disease of newborn horses. R. equi can also infect humans with AIDS or who are otherwise immunocompromized.[13] [14]

Topically applied gallium maltolate has been studied for use in neuropathic pain (severe postherpetic neuralgia and trigeminal neuralgia).[15] It has been hypothesized that any effect on pain may be related to gallium's anti-inflammatory mechanisms, and possibly from its interactions with certain matrix metalloproteinases and substance P, whose activities are zinc-mediated and which have been implicated in the etiology of pain.[6]

External links

Notes and References

  1. Bernstein . L.R.. Tanner, T. . Godfrey, C. . Noll, B. . Chemistry and pharmacokinetics of gallium maltolate, a compound with high oral gallium bioavailability . Metal-Based Drugs. 2000 . 7 . 33–48 . 10.1155/MBD.2000.33 . 18475921 . 1 . 2365198. free.
  2. Book: Bernstein, L.R. . Gielen, M. . Tiekink, E.R.T. . Metallotherapeutic Drugs and Metal-Based Diagnostic Agents: The Use of Metals in Medicine. Wiley . New York . 978-0-470-86403-6 . 259–277 . Therapeutic gallium compounds. https://www.gallixa.com/GAMReferences/MetallotherapeuticsChapter14.pdf . 2005.
  3. Chitambar, C.R. . Purpi, D.P. . Woodliff, J. . Yang, M. . Wereley J.P. . Development of Gallium Compounds for Treatment of Lymphoma: Gallium Maltolate, a Novel Hydroxypyrone Gallium Compound, Induces Apoptosis and Circumvents Lymphoma Cell Resistance to Gallium Nitrate . J. Pharmacol. Exp. Ther. . 2007 . 322 . 1228–1236 . 10.1124/jpet.107.126342 . 17600139 . 3. 12427694 .
  4. Chua, M.-Z. . Bernstein, L.R. . Li, R. . So, S.K. . Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma. Anticancer Research . 2006 . 26 . 1739–1743 . 16827101 . 3A.
  5. Bernstein . L.R. . Mechanisms of therapeutic activity for gallium . Pharmacol. Rev. . 1998 . 50 . 665–682 . 9860806 . 4.
  6. Encyclopedia: Gallium, therapeutic effects . Encyclopedia of Metalloproteins . Bernstein . Lawrence . Kretsinger . R.H. . Uversky . V.N. . Permyakov . E.A. . 2013 . 823–835 . Springer . New York . 978-1-4614-1532-9 .
  7. Chitambar, C.R. . Gallium-containing anticancer compounds . Future Med Chem . 4. 1257–1272. 2012 . 22800370 . 10. 10.4155/fmc.12.69 . 3574811.
  8. Kaneko, Y. . Thoendel, M. . Olakanmi, O. . Britigan, B.E. . Singh, P.K. . The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity . J. Clin. Invest. . 117 . 877–888 . 2007 . 10.1172/JCI30783 . 17364024 . 4 . 1810576.
  9. Parsek, M. . Singh, P. . Bacterial biofilms: an emerging link to disease pathogenesis . Annu. Rev. Microbiol. . 57 . 677–701 . 2003 . 14527295 . 10.1146/annurev.micro.57.030502.090720.
  10. DeLeon K. . Balldin F. . Watters C. . Hamood A. . Griswold J. . Sreedharan S. . Rumbaugh K.P. . Gallium maltolate treatment eradicates Pseudomonas aeruginosa infection in thermally injured mice. Antimicrobial Agents and Chemotherapy. 53. 1331–1337. 2009. 10.1128/AAC.01330-08. 19188381. 4. 2663094.
  11. Tovar-García. Arturo. Angarita-Zapata. Vanesa. Cazares. Adrián. Jasso-Chávez. Ricardo. Belmont-Díaz. Javier. Sanchez-Torres. Viviana. López-Jacome. Luis Esaú. Coria-Jiménez. Rafael. Maeda. Toshinari. García-Contreras. Rodolfo. 2020-04-01. Characterization of gallium resistance induced in a Pseudomonas aeruginosa cystic fibrosis isolate. Archives of Microbiology. en. 202. 3. 617–622. 10.1007/s00203-019-01777-y. 31773196. 2020ArMic.202..617T . 208302170. 1432-072X.
  12. García-Contreras. Rodolfo. Lira-Silva. Elizabeth. Jasso-Chávez. Ricardo. Hernández-González. Ismael L.. Maeda. Toshinari. Hashimoto. Takahiro. Boogerd. Fred C.. Sheng. Lili. Wood. Thomas K.. Moreno-Sánchez. Rafael. December 2013. Isolation and characterization of gallium resistant Pseudomonas aeruginosa mutants. International Journal of Medical Microbiology. en. 303. 8. 574–582. 10.1016/j.ijmm.2013.07.009. 23992635.
  13. Harrington, J.R. . Martens, R.J. . Cohen, N.D. . Bernstein, L.R. . Antimicrobial activity of gallium against virulent Rhodococcus equi in vitro and in vivo . J. Vet. Pharmacol. Ther. . 29 . 121–127 . 2006 . 10.1111/j.1365-2885.2006.00723.x . 16515666 . 2.
  14. Martens, R.J. . Mealey, K. . Cohen, N.D. . Harrington, J.R. . Chaffin, M.K. . Taylor, R.J. . Bernstein, L.R. . Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals . Am. J. Vet. Res. . 68 . 1041–1044 . 2007. 10.2460/ajvr.68.10.1041 . 17916007 . 10. free .
  15. Encyclopedia: Gallium, therapeutic effects . Encyclopedia of Metalloproteins . Bernstein . Lawrence . Kretsinger . R.H. . Uversky . V.N. . Permyakov . E.A. . 2013 . 823–835 . Springer . New York . 978-1-4614-1532-9 .

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