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The action of Lonidamine (LND), a dichlorinated derivative of indazole-3-carboxylic acid, on the membrane and cytoskeleton of Ehrlich tumor cells was investigated. A remarkable alteration in the molecular organization of the plasma membrane was observed. In particular, changes of plasma membrane and mitochondrial membrane protein distribution were induced by the drug. These membrane alterations were positively related to a rearrangement of microfilaments. In particular, characteristic ring-like structures of actin filaments were observed after 8 h of LND treatment. Intracellular calcium imbalance appeared-to be necessary to produce such peculiar structures. In fact, the administration of a calcium ionophore prevented the actin modifications induced by LND treatment while the simultaneous exposure to the antineoplastic drug verapamil, also considered a calcium channel blocker, was ineffective. The results reported herein suggest that the cytoskeleton as well as cell membranes might be involved in the cytotoxic action of LND and that they could share a common mechanism related to the calcium homeostasis. Moreover, Ehrlich tumor cells display a specific, peculiar rearrangement of F-actin filaments which can be considered as a marker effect of LND.