Response to ALA-based PDT in an immortalised normal breast cell line and its counterpart transformed with the Ras oncogene

Rodríguez, Lorena; DiVenosa, G; Batlle, Alcira; MacRobert, Alexander J.; Casas, Adriana

doi:10.1039/b704235c

Cited by 16 publications

(15 citation statements)

References 25 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, it is more resistant to PDT, particularly when low prophotosensitizer concentrations are used. This feature has been previously observed by our group for the mammary cell line pair HB4a and HB4a-Ras (48), showing that overexpression of RAS oncogene confers resistance to ALA-PDT, independent of the amount of porphyrins synthesized. We were therefore intrigued to explore the effectiveness of prodrugs that are proven to perform significantly better than ALA in normal cell lines in this clinically relevant oncogenic system.…”

Section: Discussionsupporting

confidence: 59%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

The use of endogenous protoporphyrin IX generated after administration of 5-aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50-to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine-tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic. Mol Cancer Ther; 14(2); 440-51. Ó2014 AACR.

show abstract

Section: Discussionsupporting

confidence: 59%

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Venosa

Vallecorsa

Giuntini

et al. 2015

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

show abstract

“…16,23,29 Only one other in vitro study has compared PpIX production in a breast cancer and corresponding normal cell line. Specifically, Rodriguez et al 29 showed that HB4-A R-ras breast cancer cell lines had higher PpIX fluorescence compared to immortalized cells not transfected with the Ras oncogene.…”

Section: Discussionmentioning

confidence: 99%

“…43 Previous studies illustrate that ALA-induced PpIX has the capability to differentially detect breast cancer in multiple biological model systems. 18,20,29,30,36,40 Fluorescence quantification of PpIX in breast cancer cell lysates treated with ALA was higher as compared to patient-matched normal cell lysates treated with ALA in explanted cell cultures from five breast cancer patients. 28 Studies on an in vivo animal model have shown that ALA-induced fluorescence can be used to enhance early detection of neoplastic and metastatic tissue from normal tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Addition of exogenous ALA causes a preferential accumulation of protoporphyrin IX ͑PpIX͒ in cancerous cells when compared to normal cells. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][33][34][35][36]39,40 PpIX is naturally produced by all nucleated cells during the heme cycle and meticulously controlled to prevent its natural accumulation. 37 This negative feedback system is thought to be modified in cancerous tissues due to ͑i͒ enzymatic defects that lead to an increase in protoporphyrinogen IX oxidase and/or ͑ii͒ reduced activity of ferrochelatase.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Preferential accumulation of 5-aminolevulinic acid-induced protoporphyrin IX in breast cancer: a comprehensive study on six breast cell lines with varying phenotypes

et al. 2010

View full text Add to dashboard Cite

Abstract. We describe the potential of 5-aminolevulinic acid ͑ALA͒-induced protoporphyrin IX ͑PpIX͒ fluorescence as a source of contrast for margin detection in commonly diagnosed breast cancer subtypes. Fluorescence intensity of PpIX in untreated and ALA-treated normal mammary epithelial and breast cancer cell lines of varying estrogen receptor expression were quantitatively imaged with confocal microscopy. Percentage change in fluorescence intensity integrated over 610-700 nm ͑attributed to PpIX͒ of posttreated compared to pretreated cells showed statistically significant differences between four breast cancer and two normal mammary epithelial cell lines. However, a direct comparison of post-treatment PpIX fluorescence intensities showed no differences between breast cancer and normal mammary epithelial cell lines due to confounding effects by endogenous fluorescence from flavin adenine dinucleotide ͑FAD͒. Clinically, it is impractical to obtain pre-and post-treatment images. Thus, spectral imaging was demonstrated as a means to remove the effects of endogenous FAD fluorescence allowing for discrimination between posttreatment PpIX fluorescence of four breast cancer and two normal mammary epithelial cell lines. Fluorescence spectral imaging of ALAtreated breast cancer cells showed preferential PpIX accumulation regardless of malignant phenotype and suggests a useful contrast mechanism for discrimination of residual cancer at the surface of breast tumor margins.

show abstract

“…We have found that Ras oncogene confers resistance to ALA-PDT [106] as well as PDT with other PS such as PII, merocyanine 540 (MC540), BPD-MA, acridine orange and m-THPC [107] (Fig. 6).…”

Section: Dna Alterations and Gene Expressionmentioning

confidence: 99%

Mechanisms of Resistance to Photodynamic Therapy

Casas¹,

Venosa²,

Hasan³

et al. 2011

CMC

286

215

View full text Add to dashboard Cite

Photodynamic therapy (PDT) involves the administration of a photosensitizer (PS) followed by illumination with visible light, leading to generation of reactive oxygen species. The mechanisms of resistance to PDT ascribed to the PS may be shared with the general mechanisms of drug resistance, and are related to altered drug uptake and efflux rates or altered intracellular trafficking. As a second step, an increased inactivation of oxygen reactive species is also associated to PDT resistance via antioxidant detoxifying enzymes and activation of heat shock proteins. Induction of stress response genes also occurs after PDT, resulting in modulation of proliferation, cell detachment and inducing survival pathways among other multiple extracellular signalling events. In addition, an increased repair of induced damage to proteins, membranes and occasionally to DNA may happen. PDT-induced tissue hypoxia as a result of vascular damage and photochemical oxygen consumption may also contribute to the appearance of resistant cells. The structure of the PS is believed to be a key point in the development of resistance, being probably related to its particular subcellular localization. Although most of the features have already been described for chemoresistance, in many cases, no cross-resistance between PDT and chemotherapy has been reported. These findings are in line with the enhancement of PDT efficacy by combination with chemotherapy. The study of cross resistance in cells with developed resistance against a particular PS challenged against other PS is also highly complex and comprises different mechanisms. In this review we will classify the different features observed in PDT resistance, leading to a comparison with the mechanisms most commonly found in chemo resistant cells.

show abstract

Response to ALA-based PDT in an immortalised normal breast cell line and its counterpart transformed with the Ras oncogene

Cited by 16 publications

References 25 publications

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

The Use of Dipeptide Derivatives of 5-Aminolaevulinic Acid Promotes Their Entry to Tumor Cells and Improves Tumor Selectivity of Photodynamic Therapy

Preferential accumulation of 5-aminolevulinic acid-induced protoporphyrin IX in breast cancer: a comprehensive study on six breast cell lines with varying phenotypes

Mechanisms of Resistance to Photodynamic Therapy

Contact Info

Product

Resources

About