Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

Abstract

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.

Mitochondrial complex I inhibitor deguelin induces metabolic reprogramming and sensitizes vemurafenib‐resistant BRAFV600E mutation bearing metastatic melanoma cells

“…We were surprised to see a trend in increased Akt activation in our phospho-array data as deguelin has been shown to inhibit Akt activation and signaling. 36,37 Additional validation by immunoblotting further confirmed the initial results from our phospho-array where we observed either an increase in Akt-phosphorylation at the residue S473 or no difference at residue T308. The contradictory results observed could be due to the early time points that were the focus of the present study as time kinetics for deguelin's inhibition have been previously done in the context of H460 lung cancer cells and only show a decrease after 24 hours of treatment at both phosphorylation sites.…”

“…We were surprised to see a trend in increased Akt activation in our phospho‐array data as deguelin has been shown to inhibit Akt activation and signaling . Additional validation by immunoblotting further confirmed the initial results from our phospho‐array where we observed either an increase in Akt‐phosphorylation at the residue S473 or no difference at residue T308.…”

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

“…Inhibition of c‐MYC by heat shock protein 90 (Hsp90) inhibitors might indicate the synergy between deguelin and fludarabine. Postulated mechanisms include downregulation of antiapoptotic proteins as a result of Akt/NF‐κB inhibition or downregulation of DNA repair enzymes and checkpoint regulators, which limits the capacity of CLL cells to repair fludarabine‐induced DNA damage …”

“…Postulated mechanisms include downregulation of antiapoptotic proteins as a result of Akt/NF-κB inhibition or downregulation of DNA repair enzymes and checkpoint regulators, which limits the capacity of CLL cells to repair fludarabine-induced DNA damage. 60 Both Akt/NF-κB inhibition and reinforcement of fludarabine-induced DNA damage take place in CLL cells treated with deguelin and fludarabine. 60 Exploiting the synergistic effect of deguelin with existing cytotoxic agents that are currently used for the treatment of various forms of cancer may thus represent a valuable therapeutic strategy.…”

“…Both Akt/NF‐κB inhibition and reinforcement of fludarabine‐induced DNA damage take place in CLL cells treated with deguelin and fludarabine . Exploiting the synergistic effect of deguelin with existing cytotoxic agents that are currently used for the treatment of various forms of cancer may thus represent a valuable therapeutic strategy.…”