Microfilament depletion and circumvention of multiple drug resistance by sphinxolides

Xinqun Zhang, Luigi Minale, Angela Zampella, Charles Smith

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Sphinxolides, a newly described family of cytotoxins from the New Caledonian sponge Neosiphonia superstes, bear structural resemblance to scytophycins. We now demonstrate that the cytotoxicity of sphinxolides is associated with cell cycle arrest in G2-M and induction of apoptosis. Like scytophycins and cytochalasins, sphinxolides caused rapid loss of microfilaments in cultured cells, without affecting microtubule organization. Microfilament reassembly was very slow after removal of the sphinxolide, consistent with the slow recovery of cellular proliferation. Sphinxolides potently inhibited actin polymerization in vitro and the microfilament- dependent ATPase activity of purified actomyosin, indicating a direct effect on actin. Importantly, sphinxolides were equally cytotoxic toward MCF-7 human breast carcinoma cells and a subline which overexpresses P-glycoprotein (MCF- 7/ADR). Similarly, overexpression of the multidrug resistance-associated protein MRP by HL-60 cells did not confer resistance to the sphinxolides. These studies demonstrate that sphinxolides are potent new antimicrofilament compounds that circumvent multidrug resistance mediated by overexpression of either P-glycoprotein or MRP. Therefore, these agents may be useful in the treatment of drug-resistant tumors.

Original languageEnglish (US)
Pages (from-to)3751-3758
Number of pages8
JournalCancer Research
Volume57
Issue number17
StatePublished - Sep 1 1997

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Zhang, X., Minale, L., Zampella, A., & Smith, C. (1997). Microfilament depletion and circumvention of multiple drug resistance by sphinxolides. Cancer Research, 57(17), 3751-3758.