RESUMO
Virotherapy is a unique modality for the treatment of cancer with oncolytic viruses (OVs) that selectively infect and lyse tumor cells, spread within tumors, and activate anti-tumor immunity. Various viruses are being developed as OVs preclinically and clinically, several of them engineered to encode therapeutic proteins for tumor-targeted gene therapy. Scientists and clinicians in German academia have made significant contributions to OV research and development, which are highlighted in this review paper. Innovative strategies for "shielding," entry or postentry targeting, and "arming" of OVs have been established, focusing on adenovirus, measles virus, parvovirus, and vaccinia virus platforms. Thereby, new-generation virotherapeutics have been derived. Moreover, immunotherapeutic properties of OVs and combination therapies with pharmacotherapy, radiotherapy, and especially immunotherapy have been investigated and optimized. German investigators are increasingly assessing their OV innovations in investigator-initiated and sponsored clinical trials. As a prototype, parvovirus has been tested as an OV from preclinical proof-of-concept up to first-in-human clinical studies. The approval of the first OV in the Western world, T-VEC (Imlygic), has further spurred the involvement of investigators in Germany in international multicenter studies. With the encouraging developments in funding, commercialization, and regulatory procedures, more German engineering will be translated into OV clinical trials in the near future.
Assuntos
Vetores Genéticos , Terapia Viral Oncolítica , Vírus Oncolíticos , Pesquisa , Animais , Ensaios Clínicos como Assunto , Terapia Combinada , Avaliação Pré-Clínica de Medicamentos , Terapia Genética/métodos , Vetores Genéticos/genética , Alemanha , Humanos , Modelos Animais , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Resultado do TratamentoRESUMO
Until today effective therapies are lacking for metastatic melanoma. The death ligand TRAIL appears as promising in cancer treatment; however, melanoma cells reveal both preexisting and inducible TRAIL resistance. Here, we present evidence that the recently described indirubin derivative 8-Rha-ß enhances melanoma cell sensitivity for death ligands and overcomes resistance to TRAIL and CD95 agonists. Indirubin is known from traditional Chinese medicine and is a potent kinase inhibitor. Unraveling of apoptotic signaling pathways revealed that TRAIL resulted in a quick (within 8h) downregulation of both agonistic TRAIL receptors DR4 and DR5, in a kind of negative feed-back loop. Treatment with indirubin, however, mediated upregulation of both receptors, thus compensating this negative feed-back loop by TRAIL. Furthermore, indirubin activated intrinsic apoptosis pathways, seen in loss of mitochondrial membrane potential and release of cytochrome c. The mitochondrial response appeared as related to upregulation of Bax and Bad and to downregulation of Mcl-1. Remarkably, indirubin in combination with TRAIL was also able to overcome apoptosis resistance due to ectopic Bcl-2 overexpression. The tumor suppressor p53 appeared as master regulator of these propapoptotic changes and is the transactivator of proapoptotic proteins which was upregulated by indirubin. Taking into account the physiological role of death ligands in immune surveillance, sensitization of melanoma cells for death ligands may be supportive for an anti-tumor immune response. Furthermore, combinations with kinase inhibitors, such as indirubin 8-Rha-ß may help for a breakthrough of TRAIL-mediated strategies in melanoma.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Melanoma/tratamento farmacológico , Fosfotransferases/antagonistas & inibidores , Receptores de Morte Celular/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/química , Indóis/farmacologia , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Morte Celular/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Helleborus niger is used in the adjuvant treatment of different tumors in anthroposophical medicine. Indications include various types of brain tumors in children, as well as prostate cancer, leukemia and lymphoma. Our aim was to investigate the therapeutic effects of these extracts apart from the traditional use. PROCEDURES: : We used an aqueous whole plant extract of H. niger in different cancer and leukemia cell lines and primary cells of patients with childhood ALL and AML and identified the main mechanisms of action. RESULTS: A strong inhibition of proliferation is caused by specific apoptosis induction, which is executed via the mitochondrial pathway and caspase-3 processing. Apoptosis could be detected in lymphoma (BJAB), leukemia (Reh, Nalm6, Sup-B15) and melanoma (Mel-HO) cells and overcomes a Bcl-2-mediated block of apoptosis. In primary cells of patients with childhood ALL and AML, which were partly poor responding to doxorubicin and daunorubicin, a strong apoptosis induction was determined. In combination with the vinca alkaloid vincristine, strong synergistic effects were detected in BJAB cells. CONCLUSION: We demonstrate in vitro efficacy of H. niger extract in cells of hematological malignancies; these studies should encourage in vivo experiments.