title: Modulation of KCa channels increases anticancer drug delivery to brain tumors and prolongs survival in xenograft model.
abstract: Most anticancer drugs fail to impact patient survival since they fail to cross the blood-brain tumor barrier (BTB) at therapeutic levels. For example, Temozolomide (TMZ) exhibits some antitumor activity against brain tumors, so does Trastuzumab (Herceptin, Her-2 inhibitor), which might be effective against Her2 neu overexpressing gliomas. Nevertheless, intact BTB and active efflux system may prevent their entry to brain tumors. Previously we have shown that potassium channel agonists increased carboplatin and Her-2 neu antibody delivery in animal glioma models. Here, we studied whether potassium channel agonist increase TMZ and Herceptin delivery across the BTB to elicit antitumor activity and increase survival in nude mice with human glial tumor. The K(Ca) channel activity and expression was also evaluated in human glioma tissues. We administered NS-1619, calcium-dependent potassium (K(Ca)) channel agonist, with [(14)C]-TMZ, and quantified TMZ delivery. The results clearly demonstrate that when given systemically both TMZ and Herceptin do not cross the BTB in significant amounts, however, NS-1619 co-infusion with [(14)C]-TMZ and Herceptin resulted in enhanced drug delivery to brain-tumor cells. The combination treatment of TMZ and Herceptin also showed improved antitumor effect which was more prominent than that of either treatment alone in increasing the survival in mice with brain tumor, when co-infused with K(Ca) channel agonists. In conclusion, K(Ca) channel agonists may benefit brain tumor patients by increasing anti-neoplastic agent's delivery to brain tumors. A clinical outcome of this research is the discovery of a novel drug delivery system that circumvents the BBB/BTB to benefit brain tumor patients.
authors.affiliation: Memorial Health University Medical Center, Department of Laboratory Oncology Research, Curtis and Elizabeth Anderson Cancer Institute, Hoskins Center for Biomedical Research, Savannah, GA, USA. ningana1@memorialhealth.com
authors.forename: Nagendra S
authors.initials: NS
authors.lastname: Ningaraj
authors.forename: Umesh T
authors.initials: UT
authors.lastname: Sankpal
authors.forename: Divya
authors.initials: D
authors.lastname: Khaitan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Meister
authors.forename: Tribhawan S
authors.initials: TS
authors.lastname: Vats
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D011923:Rats, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D000077204:Temozolomide; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001562:Benzimidazoles; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; C086491:NS 1619; D003606:Dacarbazine; D000068878:Trastuzumab; D000077204:Temozolomide