title: Downregulation of STAT3 phosphorylation enhances tumoricidal effect of IL-15-activated dendritic cell against doxorubicin-resistant lymphoma and leukemia via TNF-α.
abstract: Although disputed by some, increasing evidence suggests that TNF-α synergies with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant IL-15 in combination with the STAT3 inhibitor cucurbitacin-I in a doxorubicin-resistant murine lymphoma model. The significance of the work is to understand and design effective strategies in doxorubicin resistant lymphomas. TNF-α is downregulated in dendritic cells from mice with Dalton's lymphoma and shows an inverse relationship with disease progression. Doxorubicin-resistant DL cells have elevated levels of Bcl-2 and Mcl-1 and increased phosphorylation of STAT3. These cells are refractory to dendritic cell derived TNF-α. Doxorubicin resistant Dalton's lymphoma is susceptible to dendritic cell derived TNF-α upon stimulation with the STAT3 inhibitor cucurbitacin-I, which downregulates STAT3 and other survival molecules. The combined treatment of low dose of cucurbitacin-I and rIL-15 is ineffective in mice with doxorubicin resistant Dalton's lymphoma, but a similar therapy prolongs the survival of mice transplanted with parental Dalton's lymphoma. Doxorubicin resistant Dalton's lymphoma responds to therapy with high doses of cucurbitacin-I and rIL-15. Dendritic cell derived from mice responded positively to the therapy and regained their tumoricidal properties with respect to growth inhibition and killing of DL tumor cells. Similar to DL, DC derived from CML patients are impaired in TNF-α expression and are unable to restrict the growth of drug-resistant lymphoma and leukemia cells. This combination approach could be used as a new therapeutic strategy for aggressive and highly metastatic doxorubicin resistant lymphoma.
authors.affiliation: Immunobiology Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India; Department of Zoology, The University of Burdwan, Burdwan, West Bengal, India.
authors.forename: Sumit Kumar
authors.initials: SK
authors.lastname: Hira
authors.affiliation: Department of Pathology, Burdwan Medical College, Burdwan, West Bengal, India; Department of Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Indrani
authors.initials: I
authors.lastname: Mondal
authors.affiliation: Department of Pathology, Burdwan Medical College, Burdwan, West Bengal, India.
authors.forename: Debasis
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
authors.forename: Kailash Kumar
authors.initials: KK
authors.lastname: Gupta
authors.affiliation: Immunobiology Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, Uttar Pradesh, India. Electronic address: pp_manna@yahoo.com.
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Manna
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008806:Mice, Inbred AKR; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014315:Triterpenes / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000819:agonists / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C569274:IL15 protein, human; D019409:Interleukin-15; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C038106:cucurbitacin I
keywords: Dendritic cells; Doxorubicin; Drug resistance; IL-15; STAT3; TNF-α