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Induction of immune mediators in glioma and prostate cancer cells by non-lethal photodynamic therapy.

ABSTRACT: BACKGROUND: Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malignant potential of tumor cells surviving PDT is molecularly not well defined. METHODOLOGY/PRINCIPAL FINDINGS: Here we have evaluated changes in the transcriptome of human glioblastoma (U87, U373) and human (PC-3, DU145) and murine prostate cancer cells (TRAMP-C1, TRAMP-C2) after non-lethal PDT in vitro and in vivo using oligonucleotide microarray analyses. We found that the overall response was similar between the different cell lines and photosensitizers both in vitro and in vivo. The most prominently upregulated genes encoded proteins that belong to pathways activated by cellular stress or are involved in cell cycle arrest. This response was similar to the rescue response of tumor cells following high-dose PDT. In contrast, tumor cells dealing with non-lethal PDT were found to significantly upregulate a number of immune genes, which included the chemokine genes CXCL2, CXCL3 and IL8/CXCL8 as well as the genes for IL6 and its receptor IL6R, which can stimulate proinflammatory reactions, while IL6 and IL6R can also enhance tumor growth. CONCLUSIONS: Our results indicate that PDT can support anti-tumor immune responses and is, therefore, a rational therapy even if tumor cells cannot be completely eliminated by primary phototoxic mechanisms alone. However, non-lethal PDT can also stimulate tumor growth-promoting autocrine loops, as seen by the upregulation of IL6 and its receptor. Thus the efficacy of PDT to treat tumors may be improved by controlling unwanted and potentially deleterious growth-stimulatory pathways.

SUBMITTER: Kammerer R

PROVIDER: S-EPMC3128096 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Induction of immune mediators in glioma and prostate cancer cells by non-lethal photodynamic therapy.

Kammerer Robert R Buchner Alexander A Palluch Patrick P Pongratz Thomas T Oboukhovskij Konstantin K Beyer Wolfgang W Johansson Ann A Stepp Herbert H Baumgartner Reinhold R Zimmermann Wolfgang W

PloS one 20110630 6

<h4>Background</h4>Photodynamic therapy (PDT) uses the combination of photosensitizing drugs and harmless light to cause selective damage to tumor cells. PDT is therefore an option for focal therapy of localized disease or for otherwise unresectable tumors. In addition, there is increasing evidence that PDT can induce systemic anti-tumor immunity, supporting control of tumor cells, which were not eliminated by the primary treatment. However, the effect of non-lethal PDT on the behavior and malig ...[more]

PMID: 21738796

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Project description:Glioma is the most common primary malignant brain tumor with poor survival and limited therapeutic options. The non-psychoactive phytocannabinoid cannabidiol (CBD) has been shown to be effective against glioma; however, the molecular target and mechanism of action of CBD in glioma are poorly understood. Here we investigated the molecular mechanisms underlying the antitumor effect of CBD in preclinical models of human glioma. Our results showed that CBD induced autophagic rather than apoptotic cell death in glioma cells. We also showed that CBD induced mitochondrial dysfunction and lethal mitophagy arrest, leading to autophagic cell death. Mechanistically, calcium flux induced by CBD through TRPV4 (transient receptor potential cation channel subfamily V member 4) activation played a key role in mitophagy initiation. We further confirmed TRPV4 levels correlated with both tumor grade and poor survival in glioma patients. Transcriptome analysis and other results demonstrated that ER stress and the ATF4-DDIT3-TRIB3-AKT-MTOR axis downstream of TRPV4 were involved in CBD-induced mitophagy in glioma cells. Lastly, CBD and temozolomide combination therapy in patient-derived neurosphere cultures and mouse orthotopic models showed significant synergistic effect in both controlling tumor size and improving survival. Altogether, these findings showed for the first time that the antitumor effect of CBD in glioma is caused by lethal mitophagy and identified TRPV4 as a molecular target and potential biomarker of CBD in glioma. Given the low toxicity and high tolerability of CBD, we therefore propose CBD should be tested clinically for glioma, both alone and in combination with temozolomide.Abbreviations: 4-PBA: 4-phenylbutyrate; AKT: AKT serine/threonine kinase; ATF4: activating transcription factor 4; Baf-A1: bafilomycin A1; CANX: calnexin; CASP3: caspase 3; CAT: catalase; CBD: cannabidiol; CQ: chloroquine; DDIT3: DNA damage inducible transcript 3; ER: endoplasmic reticulum; GBM: glioblastoma multiforme; GFP: green fluorescent protein; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PARP1: poly(ADP-ribose) polymerase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; SLC8A1: solute carrier family 8 member A1; SQSTM1: sequestosome 1; TCGA: The cancer genome atlas; TEM: transmission electron microscopy; TMZ: temozolomide; TRIB3: tribbles pseudokinase 3; TRPC: transient receptor potential cation channel subfamily C; TRPV4: transient receptor potential cation channel subfamily V member 4.

Project description:Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4-87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)-isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)-for their second, 9 (20.5%)-for the third or further recurrence. The median iPDT target volume was 3.34 cm3 (range, 0.50-22.8 cm3). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4-9.8) months and the median PRS was 13.0 (95% CI, 9.2-16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response.

Dataset Information

Induction of immune mediators in glioma and prostate cancer cells by non-lethal photodynamic therapy.

Publications

Induction of immune mediators in glioma and prostate cancer cells by non-lethal photodynamic therapy.

Similar Datasets

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