Saporin induces multiple death pathways in lymphoma cells with different intensity and timing as compared to ricin

Polito, Letizia; Bortolotti, Massimo; Farini, Valentina; Battelli, Maria Giulia; Barbieri, Luigi; Bolognesi, Andrea

doi:10.1016/j.biocel.2008.09.021

Cited by 71 publications

(55 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…More recent findings suggest that RIPs may also actively induce programmed cell death through multiple mechanisms [43], [55]. In this regard, BLyS-gel treatment was shown to induce moderate caspase activation and PARP cleavage, which are hallmarks of the apoptotic pathway.…”

Section: Discussionmentioning

confidence: 99%

Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

et al. 2012

View full text Add to dashboard Cite

B lymphocyte stimulator (BLyS) is a member of the TNF superfamily of cytokines. The biological activity of BLyS is mediated by three cell surface receptors: BR3/BAFF-R, TACI and BCMA. The expression of these receptors is highly restricted to B cells, both normal and malignant. A BLyS-gelonin fusion toxin (BLyS-gel) was generated consisting of the recombinant plant-derived toxin gelonin fused to the N-terminus of BLyS and tested against a large and diverse panel of B-NHL cell lines. Interestingly, B-NHL subtypes mantle cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL) and B cell precursor-acute lymphocytic leukemia (BCP-ALL) were preferentially sensitive to BLyS-gel mediated cytotoxicity, with low picomolar EC50 values. BLyS receptor expression did not guarantee sensitivity to BLyS-gel, even though the construct was internalized by both sensitive and resistant cells. Resistance to BLyS-gel could be overcome by treatment with the endosomotropic drug chloroquine, suggesting BLyS-gel may become trapped within endosomal/lysosomal compartments in resistant cells. BLyS-gel induced cell death was caspase-independent and shown to be at least partially mediated by the “ribotoxic stress response.” This response involves activation of p38 MAPK and JNK/SAPK, and BLyS-gel mediated cytotoxicity was inhibited by the p38/JNK inhibitor SB203580. Finally, BLyS-gel treatment was shown to localize to sites of disease, rapidly reduce tumor burden, and significantly prolong survival in xenograft mouse models of disseminated BCP-ALL, DLBCL, and MCL. Together, these findings suggest BLyS has significant potential as a targeting ligand for the delivery of cytotoxic “payloads” to malignant B cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

et al. 2012

View full text Add to dashboard Cite

show abstract

“…90% survival) when used with each IT. This incomplete protection prompted us to evaluate other cell death mechanisms, taking into account that: (i) saporin-S6 and some other RIPs were reported to trigger multiple death pathways [25,40] and (ii) RIP conjugation to a specific carrier can modify its intracellular routing and consequently its toxicity pattern. …”

Section: Discussionmentioning

confidence: 99%

“…Saporin-S6, as many other type 1 and type 2 RIPs, can remove adenine from various biochemical targets in vitro, including ribosomal RNA, DNA, poly(A), and poly-ADP-ribosylated proteins [22,23,24]. Most likely, saporin-S6 is able to deadenylate different substrates also in vivo, and, as a consequence, once internalized in target cells, it can trigger several death pathways, including apoptosis, necroptosis, and to a lesser extent, necrosis [25]. This multipathway killing could also depend on RIP distribution inside the cell.…”

Section: Introductionmentioning

confidence: 99%

Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells

Polito

Mercatelli

Bortolotti

et al. 2017

Toxins

Self Cite

View full text Add to dashboard Cite

Immunotoxins (ITs) are hybrid proteins combining the binding specificity of antibodies with the cytocidal properties of toxins. They represent a promising approach to lymphoma therapy. The cytotoxicity of two immunotoxins obtained by chemical conjugation of the plant toxin saporin-S6 with the anti-CD20 chimeric antibody rituximab and the anti-CD22 murine antibody OM124 were evaluated on the CD20-/CD22-positive cell line Raji. Both ITs showed strong cytotoxicity for Raji cells, but the anti-CD22 IT was two logs more efficient in killing, probably because of its faster internalization. The anti-CD22 IT gave slower but greater caspase activation than the anti-CD20 IT. The cytotoxic effect of both immunotoxins can be partially prevented by either the pan-caspase inhibitor Z-VAD or the necroptosis inhibitor necrostatin-1. Oxidative stress seems to be involved in the cell killing activity of anti-CD20 IT, as demonstrated by the protective role of the H2O2 scavenger catalase, but not in that of anti-CD22 IT. Moreover, the IT toxicity can be augmented by the contemporary administration of other chemotherapeutic drugs, such as PS-341, MG-132, and fludarabine. These results contribute to the understanding of the immunotoxin mechanism of action that is required for their clinical use, either alone or in combination with other drugs.

show abstract

“…Indeed this protein is very resistant to chemical modifications and conjugation and to blood and endosomal proteases. Moreover, saporin appears to have a wide range of possible intracellular substrates, thus triggering multiple cell death pathways [85]. This multifaceted cytotoxic mechanism renders the selection of RIP-resistant mutants impossible.…”

Section: Discussionmentioning

confidence: 99%

Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy

Polito

Bortolotti

Pedrazzi

et al. 2011

Toxins

Self Cite

View full text Add to dashboard Cite

Ribosome-inactivating proteins (RIPs) are a family of plant toxins that permanently damage ribosomes and possibly other cellular substrates, thus causing cell death. RIPs are mostly divided in two types: Type 1 RIPs that are single-chain enzymatic proteins, and type 2 RIPs that consist of an active A chain (similar to a type 1 RIP) linked to a B chain with lectin properties. RIP-containing conjugates have been used in many experimental strategies against cancer cells, often showing great efficacy in clinical trials. Saporin-S6, a type 1 RIP extracted from Saponaria officinalis L. seeds, has been extensively utilized to construct anti-cancer conjugates because of its high enzymatic activity, stability and resistance to conjugation procedures, resulting in the efficient killing of target cells. This review summarizes saporin-S6-containing conjugates and their application in cancer therapy, considering in-vitro and in-vivo studies both in animal models and in clinical trials. The review is structured on the basis of the targeting of hematological versus solid tumors and on the antigen recognized on the cell surface.

show abstract

Saporin induces multiple death pathways in lymphoma cells with different intensity and timing as compared to ricin

Cited by 71 publications

References 40 publications

Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

Fusion Toxin BLyS-Gelonin Inhibits Growth of Malignant Human B Cell Lines In Vitro and In Vivo

Two Saporin-Containing Immunotoxins Specific for CD20 and CD22 Show Different Behavior in Killing Lymphoma Cells

Immunotoxins and Other Conjugates Containing Saporin-S6 for Cancer Therapy

Contact Info

Product

Resources

About