Changes in calcium channel activity in membranes from cis-diammine-dichloroplatinum (II) -resistant and -sensitive L1210 cells
Vassilev, P.M.; Kanazirska, M.P.; Charamella, L.J.; Dimitrov, N.V.; Tien, H.T.
Cancer Research 47(2): 519-522
1987
ISSN/ISBN: 0008-5472 PMID: 2431772 Document Number: 290049
Ca2+ channels from lipid and proteolipid fractions of cisplatin-sensitive and cisplatin-resistant cells were reconstituted and characterized in bilayer lipid membranes formed at the tips of patch-clamp micropipets. The characteristics of the Ca2+ channels were typical for the endoplasmic reticulum membrane channel activity. They had a relatively large unit conductance and were modified by typical activators (nucleotides) and inhibitors (ruthenium red, verapamil). Different doses of nifedipine did not inhibit Ca2+ channel activity. A substantial difference between the single-channel properties of the two types of investigated membranes was observed. The mean open time and the open state probability of channels reconstituted in bilayer lipid membranes from the membrane components of cisplatin-resistant cells were larger than those in bilayer lipid membranes made from components of cisplatin-sensitive cells. Ruthenium red (7 X 10(-7) M) inhibited the channel activity in both types of membranes to the same level. The observed effects could be related to an increased Ca2+ release from the intracellular Ca2+ stores (endoplasmic reticulum system) accompanied by an enhanced intracytoplasmic Ca2+ concentration in cisplatin-resistant cells. These changes in the Ca2+ concentration level may be responsible for the higher antitumor drug efflux rate and the development of the drug resistance. The suggestion is made that specific inhibitors of the Ca2+ transport across the membranes of the subcellular Ca2+-storing organelles may be tested as agents for overcoming the antitumor drug resistance.