Anticancer pentamethinium salt is a potent photosensitizer inducing mitochondrial disintegration and apoptosis upon
Radovan Krejcir1, Tomas Briza2, Martin Sterba1
1RECAMO, Masaryk Memorial Cancer Institute, Žlutý kopec 7, 656 53 Brno, Czech Republic.
Abstract:
Despite progress in the development and application of novel therapeutic agents, cancer remains a major cause of death worldwide. Therefore, there is a need for new approaches to increase therapeutic options and efficiency. The metabolism of cancer cells differs from that of non-malignant cells and their mitochondria show altered activities that can be utilized as a target for drug development. Salt 1 is a low-molecular weight heterocyclic compound of the polymethine class that accumulates in the mitochondria of cancer cells and selectively disrupts their metabolism. Salt 1 leads to a non-apoptotic form of cell death in vitro that is associated with an autophagic cellular response and eventual metabolic collapse, and inhibits human tumor xenograft growth in vivo without apparent toxicity for normal cells. As a pentamethinium compound, salt 1 exhibits intrinsic fluorescence and is a candidate for photosensitization after excitation by appropriate wavelengths of light. Herein, we report that salt 1 is a potent photosensitizer, which generates a photodynamic effect and provides enhanced cytotoxicity compared to salt 1 without light exposure. Importantly, photosensitization is optimally induced by red light, which is used clinically for photosensitization and penetrates further into tissues than lower wavelengths. Cancer cells treated with non-cytotoxic doses of salt 1 and subsequently exposed to 630 nm light show severely damaged mitochondria, manifested by reduced mitochondrial membrane potential and disintegration of the mitochondrial tubular network. As a consequence, cancer cells lose their proliferative potential and die via apoptosis in the presence of light. These findings indicate that salt 1 is a promising photosensitizer with potential to be combined with 630 nm light to strengthen its efficacy in cancer therapy.
Insights
Salt 1, a novel photosensitizer, selectively targets cancer cell mitochondria. When activated by red light, it causes cancer cell death via apoptosis, offering a potent new cancer therapy option.
Area of Science:
- Biochemistry
- Oncology
- Photodynamic Therapy
Background:
- Cancer remains a leading cause of death globally, necessitating novel therapeutic strategies.
- Cancer cell metabolism and mitochondrial activity differ from normal cells, presenting therapeutic targets.
- Salt 1, a polymethine compound, accumulates in cancer cell mitochondria, disrupting their metabolism.
Purpose of the Study:
- To investigate Salt 1 as a photosensitizer for cancer treatment.
- To evaluate the efficacy of Salt 1 combined with red light for enhanced cancer cell killing.
- To elucidate the mechanism of action of Salt 1-induced photodynamic therapy.
Main Methods:
- In vitro studies of cancer cell death pathways induced by Salt 1.
- In vivo studies using human tumor xenografts in animal models.
- Assessment of mitochondrial function (membrane potential, network integrity) after Salt 1 and light exposure.
- Evaluation of Salt 1's photosensitizing properties using red light (630 nm).
Main Results:
- Salt 1 induces non-apoptotic cell death and metabolic collapse in cancer cells in vitro.
- Salt 1 inhibits tumor xenograft growth in vivo with no apparent toxicity to normal cells.
- Salt 1 acts as a potent photosensitizer, significantly enhancing cytotoxicity when exposed to red light.
- Red light (630 nm) exposure to Salt 1-treated cancer cells results in severe mitochondrial damage and apoptosis.
Conclusions:
- Salt 1 is a promising photosensitizer for cancer therapy.
- Combining Salt 1 with red light (630 nm) enhances its therapeutic efficacy by inducing apoptosis through mitochondrial damage.
- Salt 1 offers a novel approach to cancer treatment with potential for improved outcomes.
