Effects of isoprenoid analogues of SDB-ethylenediamine on multidrug resistant tumor cells alone and in combination with chemotherapeutic drugs.
Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major obstacle for successful treatment of cancer. Inhibition of Pgp transport is important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines with at least one tertiary N atom, such as verapamil, are classical PgP-blocking agents. In a search for novel accessible compounds potent against MDR tumor cells, we synthesized a series of arylalkylamines that contain isoprenoid side chains of different length. Two out of seven new analogues of the known N,N'-bis(3,4-dimethoxybenzyl)-N-solanesylethylenediamine (SDB-ethylenediamine), namely, compounds with C10 and C15 side chains, at low micromolar concentrations were preferentially toxic for several mammalian tumor cell lines that acquired MDR during prolonged drug selection. Moreover, at noncytotoxic concentrations, these compounds potently sensitized MDR cells to Pgp substrates vinblastine and adriamycin. We conclude that these analogues of SDB-ethylenediamine may have dual therapeutic advantage because (i) they are preferentially toxic for MDR cells when administered alone and (ii) they potentiate the cytotoxicity of Pgp-transported anticancer drugs.
Sidorova
Tatyana A
TA
Laboratory of Biochemical Pharmacology, N. Blokhin Cancer Center, Russian Academy of Medical Sciences, 24 Kashirskoye Shosse, 115478 Moscow, Russia. shtilaa@yahoo.com
Nigmatov
Albert G
AG
Kakpakova
Eugenia S
ES
Stavrovskaya
Alla A
AA
Gerassimova
Galina K
GK
Shtil
Alexander A
AA
Serebryakov
Edward P
EP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003561:Cytarabine / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005029:Ethylenediamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D011090:Polyenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005029:Ethylenediamines; D011090:Polyenes; D013729:Terpenes; D003561:Cytarabine; C048678:N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine; D001761:Bleomycin; D014747:Vinblastine; D004317:Doxorubicin