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Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer.

Bull-Hansen B, Berstad MB, Berg K, Cao Y, Skarpen E, Fremstedal AS, Rosenblum MG, Peng Q, Weyergang A - Oncotarget (2015)

Bottom Line: Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells.The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts.Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

ABSTRACT
HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus

PCI efficacy of MH3-B1/rGel in SK-BR-3 and SKOV-3 cellsRelative cell viability (MTT) of SK-BR-3 (A), SKOV-3 (B) and MDA-MB-468 (C) cells after PCI of 2 nM MH3-B1/rGel (incubated for 4 hrs), representative curves from three experiments, error bars = SD. (D): rGel-corrected PCI efficacy, average of three experiments, in SK-BR-3, SKOV-3 and MDA-MB-468 cells.
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Figure 3: PCI efficacy of MH3-B1/rGel in SK-BR-3 and SKOV-3 cellsRelative cell viability (MTT) of SK-BR-3 (A), SKOV-3 (B) and MDA-MB-468 (C) cells after PCI of 2 nM MH3-B1/rGel (incubated for 4 hrs), representative curves from three experiments, error bars = SD. (D): rGel-corrected PCI efficacy, average of three experiments, in SK-BR-3, SKOV-3 and MDA-MB-468 cells.

Mentions: Since high hydrolytic degradation was indicated as a potential mechanistic cause of the low MH3-B1/rGel sensitivity in the SKOV-3 cells, we hypothesized that PCI may be useful in addressing this mechanism of resistance. Studies combining PCI and MH3-B1/rGel demonstrated highly effective cytotoxicity against SKOV-3 cells and appeared to reduce the cell viability to the same extent as observed for the SK-BR-3 cells (Fig. 3A and 3B). PCI of MH3-B1/rGel was also indicated as HER2 selective when compared to PCI of non-targeted rGel (Fig. 3A and 3B) and also when comparing the PCI data for SK-BR-3 and SKOV-3 cells with those obtained with the HER2 low expressing cell line MDA-MB-468 (Fig. 3A-3C). The efficacy of PCI of MH3-B1/rGel has recently been shown to correlate well with HER2 expression [23]. PCI efficacy may be established by comparing the light dose needed to obtain LD50 with PCI with that of the photochemical treatment (PS and light) and correct the calculation for cellular differences in sensitivity to the non-targeted toxin (as described in Materials and Methods, [23]). The PCI efficacy corrected for rGel-sensitivity in the two cell lines revealed similar efficacy of PCI of MH3-B1/rGel in the resistant SKOV-3 cells as in the SK-BR-3 cells (p > 0.05) (Fig. 3D). The rGel-corrected PCI efficacy in MDA-MB-468 cells was, however, found to be 6.8- and 6.3-fold reduced compared to that in SK-BR-3 and SKOV-3 cells respectively (Fig. 3D).


Photochemical activation of MH3-B1/rGel: a HER2-targeted treatment approach for ovarian cancer.

Bull-Hansen B, Berstad MB, Berg K, Cao Y, Skarpen E, Fremstedal AS, Rosenblum MG, Peng Q, Weyergang A - Oncotarget (2015)

PCI efficacy of MH3-B1/rGel in SK-BR-3 and SKOV-3 cellsRelative cell viability (MTT) of SK-BR-3 (A), SKOV-3 (B) and MDA-MB-468 (C) cells after PCI of 2 nM MH3-B1/rGel (incubated for 4 hrs), representative curves from three experiments, error bars = SD. (D): rGel-corrected PCI efficacy, average of three experiments, in SK-BR-3, SKOV-3 and MDA-MB-468 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494949&req=5

Figure 3: PCI efficacy of MH3-B1/rGel in SK-BR-3 and SKOV-3 cellsRelative cell viability (MTT) of SK-BR-3 (A), SKOV-3 (B) and MDA-MB-468 (C) cells after PCI of 2 nM MH3-B1/rGel (incubated for 4 hrs), representative curves from three experiments, error bars = SD. (D): rGel-corrected PCI efficacy, average of three experiments, in SK-BR-3, SKOV-3 and MDA-MB-468 cells.
Mentions: Since high hydrolytic degradation was indicated as a potential mechanistic cause of the low MH3-B1/rGel sensitivity in the SKOV-3 cells, we hypothesized that PCI may be useful in addressing this mechanism of resistance. Studies combining PCI and MH3-B1/rGel demonstrated highly effective cytotoxicity against SKOV-3 cells and appeared to reduce the cell viability to the same extent as observed for the SK-BR-3 cells (Fig. 3A and 3B). PCI of MH3-B1/rGel was also indicated as HER2 selective when compared to PCI of non-targeted rGel (Fig. 3A and 3B) and also when comparing the PCI data for SK-BR-3 and SKOV-3 cells with those obtained with the HER2 low expressing cell line MDA-MB-468 (Fig. 3A-3C). The efficacy of PCI of MH3-B1/rGel has recently been shown to correlate well with HER2 expression [23]. PCI efficacy may be established by comparing the light dose needed to obtain LD50 with PCI with that of the photochemical treatment (PS and light) and correct the calculation for cellular differences in sensitivity to the non-targeted toxin (as described in Materials and Methods, [23]). The PCI efficacy corrected for rGel-sensitivity in the two cell lines revealed similar efficacy of PCI of MH3-B1/rGel in the resistant SKOV-3 cells as in the SK-BR-3 cells (p > 0.05) (Fig. 3D). The rGel-corrected PCI efficacy in MDA-MB-468 cells was, however, found to be 6.8- and 6.3-fold reduced compared to that in SK-BR-3 and SKOV-3 cells respectively (Fig. 3D).

Bottom Line: Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells.The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts.Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

ABSTRACT
HER2-targeted therapy has been shown to have limited efficacy in ovarian cancer despite frequent overexpression of this receptor. Photochemical internalization (PCI) is a modality for cytosolic drug delivery, currently undergoing clinical evaluation. In the present project we studied the application of PCI in combination with the HER2-targeted recombinant fusion toxin, MH3-B1/rGel, for the treatment of ovarian cancer. The SKOV-3 cell line, resistant to trastuzumab- and MH3-B1/rGel- monotherapy, was shown to respond strongly to PCI of MH3-B1/rGel to a similar extent as observed for the treatment-sensitive SK-BR-3 breast cancer cells. Extensive hydrolytic degradation of MH3-B1/rGel in acidic endocytic vesicles was indicated as the mechanism of MH3-B1/rGel resistance in SKOV-3 cells. This was shown by the positive Pearson's correlation coefficient between Alexa488-labeled MH3-B1/rGel and Lysotracker in SKOV-3 cells in contrast to the negative Pearson's correlation coefficient in SK-BR-3 cells. The application of PCI to induce the release of MH3-B1/rGel was also demonstrated to be effective on SKOV-3 xenografts. Application of PCI with MH3-B1/rGel was further found highly effective in the HER2 expressing HOC-7 and NuTu-19 ovarian cancer cell lines. The presented results warrant future development of PCI in combination with MH3-B1/rGel as a novel therapeutic approach in preclinical models of ovarian cancer.

No MeSH data available.


Related in: MedlinePlus