The role of voltage gated T-type Ca2+ channel isoforms in mediating "capacitative" Ca2+ entry in cancer cells.
The mechanism by which Ca2+ enters electrically non-excitable cells is unclear. The sensitivity of the Ca2+ entry pathway in electrically non-excitable cells to inhibition by extracellular Ni2+ was used to direct the synthesis of a library of simple, novel compounds. These novel compounds inhibit Ca2+ entry into and, consequently, proliferation of several cancer cell lines. They showed stereoselective inhibition of proliferation and Ca2+ influx with identical stereoselective inhibition of heterologously expressed Cav3.2 isoform of T-type Ca2+ channels. Proliferation of human embryonic kidney (HEK)293 cells transfected with the Cav3.2 Ca2+ channel was also blocked. Cancer cell lines sensitive to our compounds express message for the Cav3.2 T-type Ca2+ channel isoform, its delta25B splice variant, or both, while a cell line resistant to our compounds does not. These observations raise the possibility that clinically useful drugs can be designed based upon the ability to block these Ca2+ channels.
Gray
Lloyd S
LS
Department of Pathology, University of Virginia, P.O. Box 800214, Charlottesville, VA, USA. lsg5m@virginia.edu
Perez-Reyes
Edward
E
Gomora
Juan Carlos
JC
Gamorra
Juan Carlos
JC
Haverstick
Doris M
DM
Shattock
Michael
M
McLatchie
Linda
L
Harper
Jane
J
Brooks
Gavin
G
Heady
Tiffany
T
Macdonald
Timothy L
TL
D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology
D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D020033:Protein Isoforms; D002118:Calcium