title: Effects of cytochalasin congeners, microtubule-directed agents, and doxorubicin alone or in combination against human ovarian carcinoma cell lines in vitro.
abstract: BACKGROUND
  Although the actin cytoskeleton is vital for carcinogenesis and subsequent pathology, no microfilament-directed agent has been approved for cancer chemotherapy. One of the most studied classes of microfilament-directed agents has been the cytochalasins, mycotoxins known to disrupt the formation of actin polymers. In the present study, we sought to determine the effects of cytochalasin congeners toward human drug sensitive and multidrug resistant cell lines.
  
  
  METHODS
  SKOV3 human ovarian carcinoma and several multidrug resistant derivatives were tested for sensitivity against a panel of nine cytochalasin congeners, as well as three clinically approved chemotherapeutic agents (doxorubicin, paclitaxel, and vinblastine). In addition, verapamil, a calcium ion channel blocker known to reverse P-glycoprotein (P-gp) mediated drug resistance, was used in combination with multiple cytochalasin congeners to determine whether drug sensitivity could be increased.
  
  
  RESULTS
  While multidrug resistant SKVLB1 had increased drug tolerance (was more resistant) to most cytochalasin congeners in comparison to drug sensitive SKOV3, the level of resistance was 10 to 1000-fold less for the cytochalasins than for any of the clinically approved agents. While cytochalasins did not appear to alter the expression of ATP binding cassette (ABC) transporters, several cytochalasins appeared to inhibit the activity of ABC transporter-mediated efflux of rhodamine 123 (Rh123), suggesting that these congeners do have affinity for drug efflux pumps. Cytochalasins also appeared to significantly decrease the F/G-actin ratio in both drug sensitive and drug resistant cells, indicative of marked microfilament inhibition. The cytotoxicity of most cytochalasin congeners could be increased with the addition of verapamil, and the drug sensitivity of resistant SKVLB1 to the clinically approved antineoplastic agents could be increased with the addition of cytochalasins. As assessed by isobolographic analysis and Chou-Talalay statistics, cytochalasin B and 21,22-dihydrocytochalasin B (DiHCB) demonstrated notable synergy with doxorubicin and paclitaxel, warranting further investigation in a tumor-bearing mammalian model.
  
  
  CONCLUSIONS
  Cytochalasins appear to inhibit the activity of P-gp and potentially other ABC transporters, and may have novel activity against multidrug resistant neoplastic cells that overexpress drug efflux proteins.
authors.affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. mrtrendo@syr.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Trendowski
authors.affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. tdchrist@syr.edu.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Christen
authors.affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. cmacqua@hotmail.com.
authors.forename: Christopher
authors.initials: C
authors.lastname: Acquafondata
authors.affiliation: Department of Biology, Syracuse University, 107 College Place, Syracuse, NY, 13244, USA. tpfondy@syr.edu.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Fondy
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003571:Cytochalasin B / Q000737:chemistry / Q000494:pharmacology*; D003572:Cytochalasins / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005260:Female; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy*
chemical_list: D000903:Antibiotics, Antineoplastic; D003572:Cytochalasins; C031582:cytochalasin C; D003571:Cytochalasin B; D004317:Doxorubicin