About
In the laboratory, we are developing two types of anti-cancer drugs: Arf6-dependent tumor invasion inhibitors and Patched inhibitors, which function as an efflux pump conferring resistance to chemotherapy.
► Inhibition of Arf6 activation. We recently demonstrated that a tetracycline, chlortetracycline (CTC), well known for its antibiotic properties through the inhibition of protein synthesis, is capable of binding to Arf6 and inhibiting its activation. Thus, we show that CTC is capable of non-competitively inhibiting Arf6 activation. in vitro whether catalyzed by an exchange factor or spontaneous. CTC is also capable of inhibiting Arf6-dependent and EGF-stimulated cell migration as well as the collective invasion properties in 3D collagen gel culture of breast cancer cells.
3D structure modeling of the Arf6GDP-CTC complex
► Role of the Patched receptor in cancer cell resistance to chemotherapy. Cancer resistance to chemotherapy leads to tumor recurrence, metastasis, treatment failure, and all too often, patient death. We have shown that the Hedgehog Patched pathway receptor (Ptch1), which is expressed in many metastatic cancers, is a drug efflux pump and contributes to cancer cell resistance to chemotherapy. We have identified inhibitors of Patched efflux activity., and showed that these molecules increase the effectiveness of several chemotherapy drugs against cells from several types of cancer, including melanoma in vitro And in vivo, and breast cancer in vitro.Our results suggest that the use of an inhibitor of Patched efflux activity as an adjuvant to chemotherapy could increase the efficacy of treatments and the survival of patients with Patched-expressing cancers.
Schematic representation of the effect of Patched efflux activity inhibitors
Macia et al. 2021, Molecules
Fiorini & Mus-Veteau 2016, Methods Mol. Biol.
Hasanovic et al. 2018 Int. J. Cancer
Hasanovic et al. 2018 Cells
Signetti et al. 2020 Cancers
Hasanovic et al. 2020 Biomedicines
Durand et al. 2021 Molecules
Kovachka et al. 2021 Phys. Chem. Chem. Phys.
Kovachka et al. 2022 Eur. J. Med. Chem.
Feliz Morel et al. 2022 Pharmaceuticals