Fighting Hypoxia to Improve PDT

Larue, Ludivine; Myrzakhmetov, Bauyrzhan; Ben-Mihoub, Amina; Moussaron, Albert; Thomas, Noémie; Arnoux, Philippe; Baros, Francis; Vanderesse, Régis; Acherar, Samir; Frochot, Céline

doi:10.3390/ph12040163

Cited by 147 publications

(101 citation statements)

References 229 publications

(312 reference statements)

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“…Therefore, a detailed analysis should be conducted to further clarify the roles of RSKs in ABCB1-mediated PpIX efflux. Hypoxia is a common characteristic of advanced solid tumours, which reduces the efficacy of 5-ALA-PDD and PDT by different mechanisms 32 . One of them is the increased expression of HIF-1α, which in turn reduces PpIX accumulation under hypoxic conditions 17,33 .…”

Section: Discussionmentioning

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Sci Rep

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The efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and photodynamic therapy (5-ALA-PDT) is dependent on 5-ALA-induced cancer-specific accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding cassette sub-family B member 1 (ABCB1) and ferrochelatase (FECH)-catalysed PpIX conversion to haem. Here, we sought to identify the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a downstream element of MEK. HIF-1α inhibition decreased FECH activity and increased PpIX accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of PpIX accumulation in human cancer cell lines. These results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of Ras/MEK involved in the regulation of PpIX accumulation.

show abstract

Section: Discussionmentioning

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Sci Rep

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show abstract

“…Hypoxia is a common characteristic of advanced solid tumors, which reduces the efficacy of 5-ALA-PDD and PDT by different mechanisms (32). One of them is the increased expression of HIF-1α, which in turn reduces PpIX accumulation under hypoxic conditions (16, 33).…”

Section: Discussionmentioning

confidence: 99%

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Chelakkot

Liu

Yoshioka

et al. 2020

Preprint

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1The efficacy of aminolevulinic acid (5-ALA)-based photodynamic diagnosis (5-ALA-PDD) and 2 photodynamic therapy (5-ALA-PDT) is dependent on the 5-ALA-induced cancer-specific 3 accumulation of protoporphyrin IX (PpIX). We previously reported that inhibition of oncogenic 4 Ras/MEK increases PpIX accumulation in cancer cells by reducing PpIX efflux through ATP-binding 5 cassette sub-family B member 1 (ABCB1) as well as PpIX conversion to heme by ferrochelatase 6 (FECH). Here, we sought to identify the downstream pathways of Ras/MEK involved in the 7 regulation of PpIX accumulation via ABCB1 and FECH. First, we demonstrated that Ras/MEK 8 activation reduced PpIX accumulation in RasV12-transformed NIH3T3 cells and HRAS transgenic 9 mice. Knockdown of p90 ribosomal S6 kinases (RSK) 2, 3, or 4 increased PpIX accumulation in the 10 RasV12-transformed NIH3T3 cells. Further, treatment with an RSK inhibitor reduced ABCB1 11 expression and increased PpIX accumulation. Moreover, HIF-1α expression was reduced when the 12 RasV12-transformed NIH3T3 cells were treated with a MEK inhibitor, demonstrating that HIF-1α is a 13 downstream element of MEK. HIF-1α inhibition decreased the activity of FECH and increased PpIX 14 accumulation. Finally, we demonstrated the involvement of RSKs and HIF-1α in the regulation of 15 PpIX accumulation in human cancer cell lines (DLD-1, SNB-75, Hs 578T, and MDA MB 231). These 16 results demonstrate that the RSK-ABCB1 and HIF-1α-FECH axes are the downstream pathways of 17 Ras/MEK involved in the regulation of PpIX accumulation. 18 19

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“…Besides, the Eka-Putra Gusti-Ngurah-Putu team reported that PDT + lipid-platinum-chloride nanoparticles significantly reduced tumor volume by up to ~112% on the OSCC xenograft model [ 18 ]. Yet, single-modal PDT's therapeutic effect was compromised mainly because of the tumor microenvironment-related hypoxia or certain anti-oxidant defense mechanisms [ 19 ]. Therefore, strategies should be considered to overcome the hypoxia-related PDT failure.…”

Section: Introductionmentioning

confidence: 99%

Peroxidase-mimicking evodiamine/indocyanine green nanoliposomes for multimodal imaging-guided theranostics for oral squamous cell carcinoma

Zheng

Huixian

Liu

et al. 2021

Bioactive Materials

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Fighting Hypoxia to Improve PDT

Cited by 147 publications

References 229 publications

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

MEK reduces cancer-specific PpIX accumulation through the RSK-ABCB1 and HIF-1α-FECH axes

Peroxidase-mimicking evodiamine/indocyanine green nanoliposomes for multimodal imaging-guided theranostics for oral squamous cell carcinoma

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