dehydroxymethylepoxyquinomicin and Hodgkin-Disease

The NF-κB inhibitor DHMEQ has shown preclinical activity in classical Hodgkin Lymphoma (cHL). Here we evaluated if DHMEQ could affect microenvironmental interactions and formation and improve the activity of drugs used in relapsed/refractory cHL. We demonstrated that DHMEQ down-regulated the NF-κB target genes IRF4 and CD40, the secretion of IL-6, CCL5, CCL17 and generated ROS. Cytotoxicity, CD30 down-modulation and CD30 shedding by DHMEQ were prevented by ROS scavenger NAC. DHMEQ overcame stimuli from CD40 engagement and fibroblasts and enhanced doxorubicin, cisplatin and gemcitabine activity. Our results suggest that DHMEQ may be a promising agent for future therapeutic strategies in cHL.

Topics: Antineoplastic Agents; Benzamides; CD40 Antigens; Cell Line, Tumor; Chemokine CCL17; Chemokine CCL5; Cyclohexanones; Down-Regulation; Drug Synergism; Hodgkin Disease; Humans; Interferon Regulatory Factors; Interleukin-6; Ki-1 Antigen; NF-kappa B; Reactive Oxygen Species; Tumor Microenvironment

Although disturbed cytokinesis of mononuclear Hodgkin (H) cells is thought to generate Reed-Sternberg (RS) cells, differentiation of Hodgkin's lymphoma (HL) cells is not fully understood. Recent studies indicate that cells found in a side population (SP) share characteristics of cancer stem cells. In this study we identified an SP in the HL cell lines, KMH2 and L428. This SP almost entirely consists of distinct small mononuclear cells, whereas the non-SP is a mixture of relatively large cells with H or RS cell-like morphology. Culture of the small mononuclear cells in the SP from KMH2 generated a non-SP. Single cell culture of the SP cells generated large cells with H or RS cell-like morphology. We found that CD30 overexpression and constitutive nuclear factor-κB (NF-κB) activity, both of which are characteristics of HL cells, are shared between the SP and non-SP cells for both KMH2 and L428. Inhibition of NF-κB induced apoptosis in both fractions, whereas the SP cells were resistant to a conventional chemotherapeutic agent doxorubicin. The results show that HL cell lines contain an SP, that is enriched for distinct small mononuclear cells and generates larger cells with H and RS cell-like morphology. The results also stress the significance of NF-κB inhibition for eradication of HL cells.

Topics: Antibiotics, Antineoplastic; Apoptosis; Benzamides; Cell Line, Tumor; Cell Survival; Cyclohexanones; Doxorubicin; Drug Resistance; Flow Cytometry; Giant Cells; Hodgkin Disease; Humans; Immunohistochemistry; Ki-1 Antigen; Leukocytes, Mononuclear; Microscopy, Fluorescence; Neoplastic Stem Cells; NF-kappa B; Reed-Sternberg Cells

Constitutive nuclear factor kappaB (NF-kappaB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kappaB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kappaB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kappaB activation through IkappaB kinase activation in not only H-RS cell lines with wild-type IkappaBalpha, but also in those with IkappaBalpha mutations and lacking wild-type IkappaBalpha. Thus, both constitutive and inducible NF-kappaB are potential targets to treat HL. We also present the data that indicate the involvement of IkappaBbeta in NF-kappaB induction by topoisomerase inhibitors. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kappaB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gammac(null) (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NF-kappaB. Results of this study suggest that both constitutive and inducible NF-kappaB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkappaBbeta is involved in NF-kappaB activation in H-RS cells and IkappaBbeta substitutes for IkappaBalpha in H-RS cells lacking wild-type IkappaBalpha.

Topics: Animals; Apoptosis; Benzamides; Caspases; Cell Line; Cyclohexanones; Daunorubicin; Enzyme Activation; Etoposide; Hodgkin Disease; Humans; I-kappa B Kinase; I-kappa B Proteins; Leukocytes, Mononuclear; Mice; Mutation; Neoplasm Transplantation; NF-kappa B; NF-KappaB Inhibitor alpha; Reed-Sternberg Cells; Topoisomerase Inhibitors; Transplantation, Heterologous; Tumor Cells, Cultured