Photoactivation of lysosomally sequestered sunitinib after angiostatic treatment causes vascular occlusion and enhances tumor growth inhibition

Abstract

The angiogenesis inhibitor sunitinib is a tyrosine kinase inhibitor that acts mainly on the VEGF and PDGF pathways. We have previously shown that sunitinib is sequestered in the lysosomes of exposed tumor and endothelial cells. This phenomenon is part of the drug-induced resistance observed in the clinic. Here, we demonstrate that when exposed to light, sequestered sunitinib causes immediate destruction of the lysosomes, resulting in the release of sunitinib and cell death. We hypothesized that this photoactivation of sunitinib could be used as a vaso-occlusive vascular-targeting approach to treating cancer. Spectral properties of sunitinib and its lysosomal accumulation were measured in vitro. The human A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane (CAM) and the Colo-26 colorectal carcinoma model in Balb/c mice were used to test the effects of administrating sunitinib and subsequently exposing tumor tissue to light. Tumors were subsequently resected and subject to immunohistochemical analysis. In A2780 ovarian carcinoma tumors, treatment with sunitinib+light resulted in immediate specific angio-occlusion, leading to a necrotic tumor mass 24 h after treatment. Tumor growth was inhibited by 70% as compared with the control group (**P<0.0001). Similar observations were made in the Colo-26 colorectal carcinoma, where light exposure of the sunitinib-treated mice inhibited tumor growth by 50% as compared with the control and by 25% as compared with sunitinib-only-treated tumors (N≥4; P=0.0002). Histology revealed that photoactivation of sunitinib resulted in a change in tumor vessel architecture. The current results suggest that the spectral properties of sunitinib can be exploited for application against certain cancer indications.

Investigation of Metabolomic Changes in Sunitinib-Resistant Human Renal Carcinoma 786-O Cells by Capillary Electrophoresis-Time of Flight Mass Spectrometry

“…The IC 50 of the 786-O Res cells was approximately 2-fold higher than that of the 786-O Par cells, which is consistent with previous reports. 19,20) Sunitinib levels in the 786-O Res cells were found to be three times higher than those in 786-O Par cells following incubation with 10 µM sunitinib, suggesting that the 786-O Res cells retain higher amounts of sunitinib than the 786-O Par cells, rather than expelling the sunitinib into the extracellular environment (Fig. 1b).…”

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

“…To further confirm that ABCC2 contributes to drug resistance through pumping out medications, we measured sunitinib uptake in CAKI‐2 cells through the detection of its known spectral range in flow cytometry (Nowak‐Sliwinska et al ., ). The results show a near doubling of the uptake of sunitinib after the addition of MK571, from 28 044 median fluorescence intensity (MFI) to 54 421 MFI (Fig.…”

“…The spectral properties of sunitinib were noted from the previous literature (Nowak‐Sliwinska et al ., ). Brilliant violet 510 (BV510) fluorochrome was identified as having very similar light absorbance, excitation, and emission properties as sunitinib.…”

The Great Escape; the Hallmarks of Resistance to Antiangiogenic Therapy

“…We recently showed that this also applies to one of the antiangiogenic TKIs, i.e., sunitinib. Sunitinib preferentially accumulates in lysosomes of tumor cells (Gotink et al, 2011) or tumor EC (Nowak-Sliwinska et al, 2015). This process was described to be involved in acquired sunitinib resistance in renal cell cancer patients.…”

“…Exposure of sunitinib-loaded lysosomes to light of an appropriate wavelength may cause the disruption of the lysosomal membrane and release of active sunitinib into the cytoplasm. We have postulated that the combination of classic sunitinibinduced angiostasis with the re-exposure of tumor cells to sunitinib after the destruction of lysosomes may lead to a clinically applicable strategy (Adar et al, 2012;Nowak-Sliwinska et al, 2015).…”