Recombinant mistletoe lectin induces p53-independent apoptosis in tumour cells and cooperates with ionising radiation

Abstract

Mistletoe extracts are used as alternative cancer treatment in addition to standard chemotherapy and radiation treatment and have an immunostimulatory and pain-relieving effect. A direct antitumour effect of mistletoe extracts against tumour cells of lymphoid origin has been linked to the D-galactoside-specific mistletoe lectin I. In this study, we investigated the cellular effect of bacterially expressed, recombinant mistletoe lectin alone or in combination with ionising radiation in a genetically defined p53-wild-type and p53-deficient E1A/ras-transformed murine tumour cells system. Downregulation of the proliferative activity and cell killing by recombinant mistletoe lectin occurred in a clear dose response (0.1 -1 ng ml À1 ). Induction of apoptosis was p53-independent, but apoptosis-associated factor-1-dependent. Cellular treatment with lectin in combination with ionising radiation resulted in both p53-wild-type and p53-deficient tumour cells in an at least additive, antiproliferative effect and enhanced activation of caspase-3. Combined treatment with ionising radiation and lectin revealed a similar cytotoxic effect in human, p53-mutated adenocarcinoma cells. Thus, recombinant mistletoe lectin alone and in combination with ionising radiation bypasses often prevalent apoptotic deficiencies in treatment-resistant tumour cells.

Tumor-associated CD75s- and iso-CD75s-gangliosides are potential targets for adjuvant therapy in pancreatic cancer

“…The CD75s-ganglioside specific viscumin and its recombinant counterpart rViscumin, both being under clinical investigation as potential antitumor drugs, are of particular interest due to their cancer-destructive potential. Besides their primordial antitumor activity on tumor cell lines including multidrug-resistant human cancer cell lines (38), synergistic antitumoral effects of the native and recombinant lectin have been documented in numerous in vitro studies employing conventional antitumor drugs (39) and ionizing radiation treatment (40). Furthermore, rViscumin has been successfully probed in treating cancer cells in animal models in vivo (41,42).…”

Aviscumine, a recombinant ribosomal inhibitor, increases the antitumor activity of natural killer cells

“…Aviscumine is a heterodimer, which is composed of a toxic A-chain, representing a site-specific type-II ribosome-inactivating N-glycosidase, and a carbohydrate-binding subunit B, responsible for its cellular uptake (7)(8)(9). The N-glycosidase-mediated catalytic inactivation of ribosomes leads to a time-and dose-dependent inhibition of protein translation and synthesis (GI 50 , 1 ng/ml) in various human tumor cell lines (10)(11)(12), independently of cell cycle or proliferation status (9,(12)(13)(14). As well as its direct cytotoxic effect, immunomodulatory activity of aviscumine was suggested in early clinical trials in which aviscumine demonstrated a clinical efficacy in various types of solid tumor with tolerable toxicity profiles (15)(16)(17)(18); this immunomodulatory effect was presumed based on increased levels of interleukin (IL) 1β, tumor necrosis factor a (TNF-α) and interferon g (IFN-γ) detected in patient sera during treatment (15).…”

Effect of AC-264, a Novel Indole Derivative, on Apoptosis in HL-60 Cells

“…[15][16] Initiation of apoptosis is controlled by regulation of the balance a These authors equally contributed to this work. between life and death signals received by the cells.…”