Currently available treatment modalities in prostate cancer (PCa) target mature and proliferating tumor cells without affecting the tumor-initiating PCa stem cells (SCs) Many patients initially experience a positive treatment response but some develop progressive disease, including tumor recurrence, metastasis, and therapy resistance. Various focal treatments, such as phototherapy, cryotherapy, interstitial thermotherapy and dynamic high-frequency ultrasound (HIFU), are being evaluated for PCa treatment. Among photoactivatable compounds, furocoumarins possess the interesting property to be highly effective when UVA irradiated, whereas are inert in the dark, thus lacking toxicity. Furthermore, it has been suggested a potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis. In this context, this work was aimed at verifying whether photoactivation of a linear furocoumarin, 8-methoxy psoralen (8-MOP), and an angular one, trimethyl angelicin (TMA) could target PCaSCs. Other than UVA light, longer wavelengths, such as 420 nm (Vis), were investigated in order to minimize surrounding tissue damage induced by light, reduce the mutagenicity of the DNA lesions induced by furocoumarins (monoadducts over cross-links), increase light penetration into the target tissue, thus allowing the use of more convenient light sources for in vivo application. While 8-MOP was able to form both crosslinks and monoadducts under the two wavelengths, TMA demonstrated to induce only the less mutagenic monoadducts in the DNA under Vis light. Production of singlet oxygen was detected only under UVA light for the two furocumarins, while Vis light was ineffective. Superoxide anion formed as a minor component of the ROS under both lights. Biological assays were carried out on DU145 cells, a prostate cancer cell line and sphere formation was used as a model for cancer cell stemness (see figure). After irradiation with 2 J/cm2 UVA, both 1 μM 8-MOP and TMA completely abrogated sphere formation. On the contrary, upon activation with 2 J/cm2 of VIS light, TMA was more effective than 8-MOP. Indeed, sphere formation was totally inhibited by 10 μM TMA, whereas 10 μM 8-MOP had no effect. Collectively, our data suggest that TMA plus VIS may be a potential focal treatment towards PCaSCs. It will be noteworthy to ascertain whether, other than DNA lesions, other molecular targets, such signaling pathways involved in the induction and maintenance of stemness in cancer cells, could be affected.

Effectiveness of photoactivatable drugs on prostate cancer stem cells: a pilot study

Giulia Maria Cigolini;Giulio Sturaro;Maria Teresa Conconi;Giorgia Miolo
2016

Abstract

Currently available treatment modalities in prostate cancer (PCa) target mature and proliferating tumor cells without affecting the tumor-initiating PCa stem cells (SCs) Many patients initially experience a positive treatment response but some develop progressive disease, including tumor recurrence, metastasis, and therapy resistance. Various focal treatments, such as phototherapy, cryotherapy, interstitial thermotherapy and dynamic high-frequency ultrasound (HIFU), are being evaluated for PCa treatment. Among photoactivatable compounds, furocoumarins possess the interesting property to be highly effective when UVA irradiated, whereas are inert in the dark, thus lacking toxicity. Furthermore, it has been suggested a potential role of the bioactive compounds isolated from the medicinal plant Psoralea corylifolia (neobavaisoflavone and psoralidin) in prostate cancer chemoprevention through enhancement of TRAIL-mediated apoptosis. In this context, this work was aimed at verifying whether photoactivation of a linear furocoumarin, 8-methoxy psoralen (8-MOP), and an angular one, trimethyl angelicin (TMA) could target PCaSCs. Other than UVA light, longer wavelengths, such as 420 nm (Vis), were investigated in order to minimize surrounding tissue damage induced by light, reduce the mutagenicity of the DNA lesions induced by furocoumarins (monoadducts over cross-links), increase light penetration into the target tissue, thus allowing the use of more convenient light sources for in vivo application. While 8-MOP was able to form both crosslinks and monoadducts under the two wavelengths, TMA demonstrated to induce only the less mutagenic monoadducts in the DNA under Vis light. Production of singlet oxygen was detected only under UVA light for the two furocumarins, while Vis light was ineffective. Superoxide anion formed as a minor component of the ROS under both lights. Biological assays were carried out on DU145 cells, a prostate cancer cell line and sphere formation was used as a model for cancer cell stemness (see figure). After irradiation with 2 J/cm2 UVA, both 1 μM 8-MOP and TMA completely abrogated sphere formation. On the contrary, upon activation with 2 J/cm2 of VIS light, TMA was more effective than 8-MOP. Indeed, sphere formation was totally inhibited by 10 μM TMA, whereas 10 μM 8-MOP had no effect. Collectively, our data suggest that TMA plus VIS may be a potential focal treatment towards PCaSCs. It will be noteworthy to ascertain whether, other than DNA lesions, other molecular targets, such signaling pathways involved in the induction and maintenance of stemness in cancer cells, could be affected.
2016
Book of Abstracts of the Joint Congress of the French and Italian Photochemists and Photobiologists
Joint Congress of the French and Italian Photochemists and Photobiologists
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3298907
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