Abstract
Cancer cells are considered to express primary drug resistance, yet chemotherapeutics are the front line of cancer treatments and have achieved great successes. In time, most neoplastic cells develop secondary resistance to chemotherapy, which remains the major obstacle to cancer treatment. Progressive multi-drug resistance develops by upregulation of a large family of drug ABC transporters, such as the P-glycoprotein.
ALA-PDT is a non-invasive cancer therapy that is limited to organs that are accessible to light and it is dependent on the biosynthesis of the natural photosensitizer PpIX, largely detached of sensitizer efflux by transporters. The action mechanism of ALA-PDT starts by light irradiation and production of singlet oxygen as the toxic molecule, which hits the tumor at many subcellular targets and induces both necrosis and apoptosis, the Achilles heel of a tumor. Recently, it was suggested that PDT, based on multifunctional ALA-prodrugs, may overcome drug resistance of tumors.
Multifunctional acyloxyalkyl ester prodrugs induce efficient PpIX synthesis due to upregulated PpIX biosynthesis and efficient photodynamic killing of cancer cells. One of these prodrugs, AlaAcBu, releases three active products: ALA, acetaldehyde and butyric acid. They stimulate independent pathways through activation of specific biochemical routes; ALA stimulates PpIX synthesis and PDT, acetaldehyde endorses dark-tumor cytotoxicity and butyric acid inhibits histone deacetylase, leading to gene expression and tumor differentiation. All are targeted to boost anticancer actions and to reduce tumor recurrence.
We describe here a protocol for boosting PpIX synthesis in Multi Drug Resistant cells by two rounds of ALA exposures. The first induces synthesis of dipyrromethane from ALA, which is essential for PBGD activity, while the second provides the precursor for PpIX synthesis and photodynamic cell killing.
In conclusion, new ALA delivery protocols and novel generations of multifunctional ALA prodrugs may render ALA-PDT into a more potent method in the front line cancer therapy. We believe that the future of ALA-PDT will involve the introduction of combinatory concepts of multifunctional ALA prodrugs to maximize sensitizer biosynthesis and to hit tumors in multiple subcellular targets independent of multi-drug resistance.
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Abbreviations
- ALA:
-
5-amino levulinic acid
- ALAD:
-
ALA dehydratase
- DPM:
-
Dipyrromethane
- MDR:
-
Multidrug resistance
- PBGD:
-
Porphobilinogen deaminase
- PpIX:
-
Protoporphyrin IX
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Malik, Z., Nudelman, A., Ehrenberg, B. (2015). Mechanisms of Tumor Cell Resistance to ALA-PDT. In: Rapozzi, V., Jori, G. (eds) Resistance to Photodynamic Therapy in Cancer. Resistance to Targeted Anti-Cancer Therapeutics, vol 5. Springer, Cham. https://doi.org/10.1007/978-3-319-12730-9_10
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DOI: https://doi.org/10.1007/978-3-319-12730-9_10
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