cucurbitacin-i and Lymphoma

Dendritic cell (DC)-based therapies could be important strategies for lymphoma treatment.. AKR/J mice with Dalton's lymphoma were treated with recombinant interleukin-15 (rIL-15)-activated autologous DCs and pulsed with whole tumor cell lysates in the presence or absence of suboptimal doses of the STAT3 inhibitor cucurbitacin I. One group of treated mice received an additional dose of rIL-15 to boost the DC-based adoptive cell therapy (ACT). Kaplan-Meier survival analysis and multiple immunologic and enzymatic parameters were assessed to demonstrate the efficacy of the vaccination protocol.. Therapy with tumor lysate-pulsed, rIL-15-activated DCs plus cucurbitacin I significantly prolongs the survival of tumor-bearing mice but fails to provide a complete cure. Additional treatment of vaccinated mice with rIL-15 dramatically improves the therapeutic efficacy and provides a lifelong cure with no relapse. DCs derived from the surviving vaccinated mice regained their anti-tumor potential against the lymphoma cells with respect to growth inhibition and cytotoxicity. Both cluster of differentiation (CD)4(+) and CD8(+) T cells were mobilized in metastatic organs of successfully vaccinated mice in large numbers and demonstrated antigen-specific proliferation and tumor cell cytotoxicity. ACT also augments DC function by upregulating tumor necrosis factor-related apoptosis-inducing ligand and tumor necrosis factor-α expression. In addition, combinatorial immunotherapy restores the levels of antioxidant enzymes and liver function enzyme activities that are severely repressed in untreated tumor-bearing mice.. Effective vaccination for a complete cure against aggressive lymphoma requires DC-based ACT in combination with chemotherapy and cytokine therapy.

Topics: Animals; Antioxidants; Blood Glucose; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Extracts; Cell Proliferation; Cytokines; Cytotoxicity, Immunologic; Dendritic Cells; Immunotherapy; Interleukin-15; Lymphoma; Mice, Inbred AKR; Neoplasm Metastasis; Organ Specificity; Remission Induction; Survival Analysis; TNF-Related Apoptosis-Inducing Ligand; Triterpenes; Tumor Necrosis Factor-alpha; Vaccination

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.

Topics: Animals; Antineoplastic Agents; Coculture Techniques; Cytotoxicity, Immunologic; Dendritic Cells; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-15; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphocytes; Lymphoma; Mice; Mice, Inbred AKR; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Recombinant Proteins; Signal Transduction; STAT3 Transcription Factor; Survival Analysis; Triterpenes; Tumor Necrosis Factor-alpha