Activation of KATP channels increases anticancer drug delivery to brain tumors and survival

Nagendra S. Ningaraj, Umesh T. Sankpal, Divya Khaitan, Edward A. Meister, Trib Vats

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Several anticancer drugs are ineffective against brain tumor and do not impact patient survival because they fail to cross the blood-brain tumor barrier (BTB) effective levels. One such agent temozolomide is commonly used in brain tumor patients, which works better when combined with radiation or other anticancer agents. Likewise, trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2/neu over expressing gliomas may work well when combined with temozolomide. Nonetheless, both drugs do not cross the BTB to significantly impact patient survival. Beforehand we showed that potassium channel agonists when intracarotidly administered increased carboplatin and Her-2 antibody delivery in animal glioma models by triggering formation of brain vascular endothelial transcytotic vesicles. In this study, we investigated whether, intravenously administered, ATP-sensitive potassium channel (KATP) activator (minoxidil sulfate; MS) increases temozolomide and Herceptin delivery to brain tumors to induce anti-tumor activity and increase survival in nude mice with Glioblastoma multiforme (GBM) cells. The results clearly demonstrate that when given intravenously temozolomide crosses BTB at a relatively low amount while Herceptin failed to cross the BTB. However, MS co-infusion with [14C]-temozolomide or fluorescently labeled-Herceptin resulted in improved and selective drug delivery to brain tumor. We also showed that combination treatment with temozolomide and Herceptin has enhanced anti-tumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with GBM when co-infused with MS. Therefore, brain tumor patients may be benefited when anti-neoplastic agent delivery is increased selectively to the brain tumors using KATP channel agonists.

Original languageEnglish
Pages (from-to)188-193
Number of pages6
JournalEuropean Journal of Pharmacology
Volume602
Issue number2-3
DOIs
StatePublished - 14 Jan 2009

Fingerprint

temozolomide
KATP Channels
Brain Neoplasms
Survival
Pharmaceutical Preparations
Glioblastoma
Glioma
Carboplatin
Potassium Channels
Blood-Brain Barrier
Nude Mice
Antineoplastic Agents
Blood Vessels
Trastuzumab
Neoplasms
Animal Models
Radiation

Keywords

  • Blood-brain barrier
  • Glioblastoma multiforme
  • Herceptin
  • Minoxidil sulfate
  • Potassium channel
  • Temozolomide

Cite this

Ningaraj, Nagendra S. ; Sankpal, Umesh T. ; Khaitan, Divya ; Meister, Edward A. ; Vats, Trib. / Activation of KATP channels increases anticancer drug delivery to brain tumors and survival. In: European Journal of Pharmacology. 2009 ; Vol. 602, No. 2-3. pp. 188-193.
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Activation of KATP channels increases anticancer drug delivery to brain tumors and survival. / Ningaraj, Nagendra S.; Sankpal, Umesh T.; Khaitan, Divya; Meister, Edward A.; Vats, Trib.

In: European Journal of Pharmacology, Vol. 602, No. 2-3, 14.01.2009, p. 188-193.

Research output: Contribution to journalArticle

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