Photochemical activation of the recombinant HER2-targeted fusion toxin MH3-B1/rGel; Impact of HER2 expression on treatment outcome

Bull-Hansen, Bente; Cao, Yu; Berg, Kristian; Skarpen, Ellen; Rosenblum, Michael G.; Weyergang, Anette

doi:10.1016/j.jconrel.2014.03.014

Cited by 21 publications

(32 citation statements)

References 35 publications

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“…2C, is utilized to enhance the cytosolic delivery of several types of macromolecular drugs (e.g. protein-based toxins and targeting toxins) and some chemotherapeutics for cancer therapy [21]; [28]; [57]; [58]; [59]. Regardless of PDT sensitivity, which may vary with accumulation, localization and/or death and survival signalling of treated cancer cells, we have demonstrated that PCI of ribosomal inactivating toxins (e.g.…”

Section: Discussionmentioning

confidence: 99%

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Olsen

Weyergang

Edwards

et al. 2017

Biochemical Pharmacology

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Here we report on the induction of resistance to photodynamic therapy (PDT) in the ABCG2-high human breast cancer cell line MA11 after repetitive PDT, using either Pheophorbide A (PhA) or di-sulphonated meso-tetraphenylchlorin (TPCS) as photosensitizer. Resistance to PhA-PDT was associated with enhanced expression of the efflux pump ABCG2. TPCS-PDT-resistance was neither found to correspond with lower TPCS-accumulation nor reduced generation of reactive oxygen species (ROS). Cross-resistance to chemotherapy (doxorubicin) or radiotherapy was not observed. TPCS-PDT-resistant cells acquired a higher proliferation capacity and an enhanced expression of EGFR and ERK1/2. p38 MAPK was found to be a death-signalling pathway in the MA11 cells post TPCS-PDT, contrasting the MA11/TR cells in which PDT generated a sustained phosphorylation of p38 that had lost its death-mediated signalling, and an abrogated activation of its downstream effector MAPKAPK2. No difference in apoptosis, necrosis or autophagy responses was found between the treated cell lines. Development of TPCS-PDT resistance in the MDA-MB-231 cell line was also established, however, p38 MAPK did not play a role in the PDT-resistance. MCF-7 cells did not develop TPCS-PDT-resistance. Photochemical internalisation (PCI) of 1 pM of EGF-saporin induced equal strong cytotoxicity in both MA11 and MA11/TR cells. In conclusion, loss of p38 MAPK-inducing death signalling is the main mechanism of resistance to TPCS-PDT in the MA11/TR cell line. This work provides mechanistic knowledge of intrinsic and acquired PDT-resistance which is dependent on choice of photosensitizer, and suggests PCI as a rational therapeutic intervention for the elimination of PDT-resistant cells.

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Section: Discussionmentioning

confidence: 99%

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Olsen

Weyergang

Edwards

et al. 2017

Biochemical Pharmacology

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“…5A and 5A2), the formula must be corrected to65 :− = ( )Where IC 50 is the macromolecular drug concentration, as measured in µM, which inhibits 50 % of the biologic activity of its target or reduces the cell viability to 50 %.The efficacy of a targeting drug (without PCI) is often represented by the targeting index (TI) assessed by; set light dose. These studies have also indicated PCI to have similar or even increased efficacy in resistant cancers compared to non-resistant models.…”

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confidence: 99%

“…). The cellular response to PCI of MH3-B1/rGel has been reported to correlate positively to HER2 expression demonstrating HER2 specificity65 . A promising indication here is ovarian cancer, where HER2-targeted TKIs and mAbs have failed to demonstrate any clinical benefit despite HER2 being over expressed in lines exert a more rapid HER2 endocytosis compared to HER2 high and dependent cell lines[66][67][68] .…”

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confidence: 99%

Photochemical activation of drugs for the treatment of therapy-resistant cancers

Weyergang

Berstad

Bull-Hansen

et al. 2015

Photochem Photobiol Sci

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Resistance to chemotherapy, molecular targeted therapy as well as radiation therapy is a major obstacle for cancer treatment. Cancer resistance may be exerted through multiple different mechanisms which may be orchestrated as observed in multidrug resistance (MDR). Cancer resistance may be intrinsic or acquired and often leaves patients without any treatment options. Strategies for alternative treatment modalities for resistant cancer are therefore highly warranted. Photochemical internalization (PCI) is a technology for cytosolic delivery of macromolecular therapeutics based on the principles of photodynamic therapy (PDT). The present report reviews the current knowledge of PCI of therapy-resistant cancers. In summary, PCI may be able to circumvent several of the major mechanisms associated with resistance towards chemotherapeutics including increased expression of drug efflux pumps, altered intracellular drug distribution and increased ROS scavenging. Current data also suggest PCI of targeted toxins as highly effective in cancers resistant to clinically available targeted therapy such as monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). PCI may therefore, in general, represent a future treatment option for cancers resistant to other therapies.

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“…Antibodies can deliver cytotoxic agents, including proteins, radionuclide and small molecules, into malignant cells by targeting overexpressed receptors on cell surface . Bull‐Hansen et al targeted human epidermal growth factor receptor HER2, which is overexpressed in 20% – 30% of breast tumors, with HER2 single‐chain antibody fragment MH3‐B1 fused type I RIP toxin gelonin (rGel) . Tests in four breast cancer cell lines with different HER2 expression levels (MDA‐MB‐231, BT‐20, Zr‐75–1 and SK‐BR‐3) showed that ∼120 times more MH3‐B1/rGel accumulated in HER2 high expressing cell line SK‐BR‐3 than HER2 low expressing cell line MDA‐MB‐231 and the IC 50 was reduced by ∼1000 time in SK‐BR‐3 while no obvious difference in IC 50 was observed between rGel and MH3‐B1/rGel in MDA‐MB‐231.…”

Section: Biomacromolecules For Anticancer Protein Deliverymentioning

confidence: 99%

“…[ 113 ] Bull-Hansen et al targeted human epidermal growth factor receptor HER2, which is overexpressed in 20% -30% of breast tumors, with HER2 single-chain antibody fragment MH3-B1 fused type I RIP toxin gelonin (rGel). [ 114 ] Tests in four breast cancer cell lines with different HER2 expression levels (MDA-MB-231, BT-20, Zr-75-1 and SK-BR-3) showed that ∼120 times more MH3-B1/rGel accumulated in HER2 high expressing cell line SK-BR-3 than HER2 low expressing cell line MDA-MB-231 and the IC 50 was reduced by ∼1000 time in SK-BR-3 while no obvious difference in IC 50 was observed between rGel and MH3-B1/rGel in MDA-MB-231. Despite the compelling targeting effi ciency of anti-body conjugated proteins, lacking a cost-effective production platform hurdled its translation to marketplace.…”

Section: Protein Nanoparticlementioning

confidence: 99%

Advances in Anticancer Protein Delivery using Micro‐/Nanoparticles

Sun

Lü

2014

Part & Part Syst Charact

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Proteins exhibiting anticancer activities, especially those capable of discriminately killing cancer cells, have attracted increasing interest in developing protein-based anticancer therapeutics. This progress report surveys recent advances in delivering anticancer proteins directly to tumor tissue for inducing apoptosis/necrosis or indirectly to antigen presenting cells for provoking immune responses. Protein delivery carriers such as inorganic particles, lipid particles, polymeric particles, DNA/protein based biomacromolecular particles as well as cell based carriers are reviewed with comments on their advantages and limitations. Future challenges and opportunities are also discussed.

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Photochemical activation of the recombinant HER2-targeted fusion toxin MH3-B1/rGel; Impact of HER2 expression on treatment outcome

Cited by 21 publications

References 35 publications

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Development of resistance to photodynamic therapy (PDT) in human breast cancer cells is photosensitizer-dependent: Possible mechanisms and approaches for overcoming PDT-resistance

Photochemical activation of drugs for the treatment of therapy-resistant cancers

Advances in Anticancer Protein Delivery using Micro‐/Nanoparticles

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