echinomycin and Skin-Neoplasms

Systemic chemotherapy is often the last resort of advanced cutaneous T-cell lymphoma (CTCL). Tumor recurrence and adverse effects of systemic chemotherapy are the main limitations.. We aim to investigate the metabolic alterations in tumor cells after CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) chemotherapy.. In advanced CTCL, CHOP chemotherapy has no survival benefit and the duration of response is significantly inferior to other canonical treatments. HIF-1α is significantly elevated in lesions of advanced MF patients as well as tumor cell line Hut78 and tumor xenograft mice model. CHOP therapy also increased glycolytic activities in a HIF-1α-dependent manner. In CTCL xenograft tumor mice model, lesional cells showed a significant increase in IL-17F after chemotherapy, shifting toward a Th17 phenotype, which process is also regulated by HIF-1α. Echinomycin, HIF-1α inhibitor, was co-administered in xenograft tumor mouse models with CHOP and showed a significant reduction in tumor growth.. CHOP chemotherapy promotes glycolysis and IL-17 pathways in a HIF-1α-dependent fashion. Furthermore, HIF-1α blockade is promising as an accompanying agent in systemic chemotherapy for patients with advanced CTCL.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclophosphamide; Doxorubicin; Echinomycin; Female; Gene Expression; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-17; Lymphoma, T-Cell, Cutaneous; Mycosis Fungoides; Neoplasm Transplantation; Prednisone; Signal Transduction; Skin Neoplasms; Th17 Cells; Up-Regulation; Vincristine

Cancer cells adapt to the stress resulting from accelerated cell growth and a lack of nutrients by activation of the autophagy pathway. Two proteins that allow cell growth in the face of metabolic stress and hypoxia are hypoxia-inducible factor-1α (HIF-1α) and heat shock protein 90 (Hsp 90). We hypothesize that chloroquine (CQ), an antimalarial drug that inhibits autophagosome function, in combination with either echinomycin, a HIF-1α inhibitor, or 17-dimethylaminoethylamino-17-dimethoxygeldanamycin (17-DMAG), an Hsp 90 inhibitor, will result in cytotoxicity in melanoma.. Multiple human melanoma cell lines (BRAF wild-type and mutant) were tested in vitro with CQ in combination with echinomycin or 17-DMAG. These treatments were performed in hypoxic (5% O2) and normoxic (18% O2) conditions. Mechanism of action was determined through Western blot of autophagy-associated proteins HIF-1α and Hsp 90.. Chloroquine, echinomycin, and 17-DMAG each induced cytotoxicity in multiple human melanoma cell lines, in both normoxia and hypoxia. Chloroquine combined with echinomycin achieved synergistic cytotoxicity under hypoxic conditions in multiple melanoma cell lines (BRAF wild-type and mutant). Western blot analysis indicated that echinomycin reduced HIF-1α levels, both alone and in combination with CQ. Changes in LC3 flux indicated inhibition of autophagy at the level of the autophagosome by CQ therapy.. Targeting autophagy with the antimalarial drug CQ may be an effective cancer therapy in melanoma. Sensitivity to chloroquine is independent of BRAF mutational status. Combining CQ with the HIF-1α inhibitor echinomycin improves cytotoxicity in hypoxic conditions.

Topics: Antibiotics, Antineoplastic; Antimalarials; Autophagy; Benzoquinones; Cell Line, Tumor; Chloroquine; Drug Therapy, Combination; Echinomycin; HSP90 Heat-Shock Proteins; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Lactams, Macrocyclic; Melanoma; Skin Neoplasms; Stress, Physiological