The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration

Abstract

Chemotherapy is one of the pillars of anti-cancer therapy. Although chemotherapeutics cause regression of the primary tumor, many chemotherapeutics are often shown to induce or accelerate metastasis formation. Moreover, metastatic tumors are largely resistant against chemotherapy. As more than 90% of cancer patients die due to metastases and not due to primary tumor formation, novel drugs are needed to overcome these shortcomings. In this study, we identified the anticancer phytochemical Rocaglamide (Roc-A) to be an inhibitor of cancer cell migration, a crucial event in metastasis formation. We show that Roc-A inhibits cellular migration and invasion independently of its anti-proliferative and cytotoxic effects in different types of human cancer cells. Mechanistically, Roc-A treatment induces F-actin-based morphological changes in membrane protrusions. Further investigation of the molecular mechanisms revealed that Roc-A inhibits the activities of the small GTPases RhoA, Rac1 and Cdc42, the master regulators of cellular migration. Taken together, our results provide evidence that Roc-A may be a lead candidate for a new class of anticancer drugs that inhibit metastasis formation.

Recent Progress on the Molecular Mechanisms of Anti-invasive and Metastatic Chinese Medicines for Cancer Therapy

“…Recently, it was reported to inhibit nasopharyngeal carcinoma cell migration and invasion in vitro through suppressing Rho GTPases including RhoA, Rac1, and Cdc42 [56]. The anti-metastatic ability of Rocaglamide-A was also recently described via inhibiting the activity of Rho GTPases RhoA, Rac1, and Cdc42 [57]. As a dietary flavonoid in Eucalyptus honey and Myrtaceae pollen, tricetin was shown to attenuate osteosarcoma cell migration via suppressing MMP-9 via p38 and Akt pathways [58].…”

Searching the Link for Better Therapeutic Combination: The Case of Tumor Cells Migration Pattern and Modality of Immunosuppression Induction at the Metastatic Site

“…Rho GTPases are members of Rho family proteins that act as intracellular transducers mediating the organization of various types of actin filaments, thus playing an important role in cells migration. Rho GTPases include many molecules such as RhoA, Rac1, and Cdc42 and have multiple effectors mainly the Rho-associated coiled coil-containing protein kinases (ROCKs) [3]. In addition to their permissive role in tumor cell migration, Rho GTPases have specific effects on collective migration by maintaining the front-rear polarity of cell clusters and the stability of cell-cell junction [4].…”

“…As for ROCK inhibitors, a drug labeled AT13148 has completed the phase I, but the results have not been reported yet. Another approach for targeting this pathway is through nonspecific commonly used drugs that have shown an inhibitory effect on the Rho GTPases pathway, such as statins and the phytochemical agent known as rocaglamide [3,6].…”

Down‐regulation of intracellular anti‐apoptotic proteins, particularly c‐FLIP by therapeutic agents; the novel view to overcome resistance to TRAIL

“…Moreover, rocaglamide suppressed production of cytokines and inhibits nuclear factor of activated T cell (NFAT) activity in peripheral blood T cells. In addition, it induced apoptosis in leukemia cells through the modulation of protein kinases activities that are activated by diverse mitogens (Becker et al, ). Likewise, the positive effect of this flavonoid was displayed in treatment of pancreatic, liver and Hodgkin's lymphomas cancers cell lines (Giaisi, Kohler, Fulda, Krammer, & Li‐Weber, ; Luan, He, He, & Chen, ; Wang, Li, Tan, & Xiao, ; Zhu et al, ).…”