The underlying signaling pathway involves Rho/ROCK and myosin to induce the actin dependent contractile force. In both processes, the actin cytoskeleton plays a central role either for the formation of protrusions or the contraction of the cell. Therefore, the actin machinery represents an attractive target to address metastatic cells. Interestingly, a large number of natural compounds bind the actin cytoskeleton and interfere with actin dynamics. Since actin is of central importance for most organisms, including parasites and fungi, nature most likely has favored the evolution of secondary metabolites which target actin one way or the other. Nevertheless, the use of these natural compounds has been neglected due to the ubiquitous occurrence of actin and possible severe side effects. However, the successful 20S-Notoginsenoside-R2 clinical use of microtubule binding agents as anti-cancer drugs mitigates this argument. An actin binding compound evolved from natural selection is Chondramide. Chondramide is a cyclodepsipeptide isolated from the myxobacterium Chondromyces crocatus. It induces actin polymerization in vitro and has only been shown to be cytotoxic but its detailed mode of action on cancer cells has not been elucidated so far. We hypothesize that metastasis can be inhibited using the actin polymerizing compound Chondramide and elucidate its potency in vitro and in vivo. Here, we can show that Chondramide inhibits cancer cell Mechlorethamine hydrochloride migration and invasion in vitro involving signaling pathways, which influence cellular contractility. Further, we demonstrate that Chondramide is capable to reduce metastasis in vivo. Cellular contractility is of utmost importance in cancer cell invasion. Classic migration depends on contractility as the cell rear has to be retracted after cell protrusion and formation of new adhesions in the migration direction. Further, the amoeboid migration of cancer cells is mostly driven by contractile force depending on Rho/ROCK signaling but not proteolysis. According to literature, the highly invasive cell line MDA-MB-231 follows the scheme of an amoeboid migration through matrigel, requiring a contractile uropod dependent on RhoA and MLC-2 activity. During this process, cells exert contractile force to the surrounding matrix. Accordingly, we observed a matrix deformation by migrating MDA-MB cells, as shown by fluorescent bead movement. This bead displacement was reduced after Chondramide treatment indicating reduced contractile force of the cell due to treatment. The observation that migration, invasion and contractility are inhibited at the same concentration of Chondramide suggests that the reduction of contractility is the underlying cause for these functional defects. The signaling cascade leading to contractility, via Rho/ROCK and myosin, is known to enhance invasion when upregulated. Chondramide treatment diminishes the activity of Rho and MLC2. Other factors like Rac1 or EGFR and its downstream factors, Akt and Erk, were not affected at same conditions. Thus, Chondramide primarily inhibits the pro-contractile signaling cascade. Interestingly, a connection between contractile force and RhoA activation is reported not only from Rho being required for contractility but also the other way around that contractile force induces RhoA activation. In this context, Vav2 has been shown to be induced by applied forces in the form of stretching in mesangial cells and Vav2 is known to be necessary for a full activation of RhoA in MDA-MB-231 cells. These observations are in line with our findings revealing that Vav2 and RhoA are less active in Chondramide treated cells. According to our in vitro data, adhesion is not yet affected at 30 nM Chondramide, while transmigration and Rho activity and phorphorylation of MLC2 are.