Investigation of the effects of denovo synthesized water-soluble phthalocyanine compounds in a pancreatic tumor model

Cancer is a major global issue and ranks among the leading causes of death worldwide. It is estimated that there are approximately twenty million cancer cases and ten million cancer-related deaths each year globally. Among cancers, pancreatic cancer has one of the highest morbidity and mortality rates, with a five-year survival rate of around 6%. At the time of diagnosis, most patients present with either metastatic or locally advanced disease. Therefore, the only curative treatment option, surgery, is not suitable for many patients. Additionally, even in patients who are eligible for surgery, survival rates remain low due to local or distant recurrences after surgery. Many chemotherapy agents are used for pancreatic cancer, but the desired results have not been achieved with these treatments. For these reasons, research into new treatment alternatives is intensively ongoing. Immunotherapy, which has been tested with successful results in the treatment of many malignancies, is also being explored for pancreatic cancers. Telomerase, an enzyme located at chromosome ends and playing a role in genomic stability, is crucial for the survival of cancer cells, and overexpression of telomerase is present in most pancreatic cancers. The inhibition of the telomerase enzyme stands out as an important therapeutic target for the elimination of cancer cells. Due to their aromatic structure and π-electron richness, phthalocyanines are highly stable, intensely colored molecules with strong thermal, chemical, and photostability. Their ability to bind to telomeric G-Quadruplex DNA makes phthalocyanines a promising research area for cancer treatment. In this study, it was aimed to determine the telomerase inhibitory activities of five different water-soluble phthalocyanine derivatives [p-quaternized ZnPc (AC-1), np-quaternized ZnPc (AC-2), Q-p-ZnPc-II (AC-3), Q-p-ZnPc-III (MC-1), Q-np-ZnPc-III (MC-2)] in pancreatic cancer cell lines (Mia-PaCa-2 and PANC-1) by investigating the expression of Telomerase reverse transcriptase (hTERT), telomere length, and telomerase protein levels. In studies conducted with PANC-1 cell lines, we observed that hTERT expression in the PANC-1 cell line decreased by 1.09-fold for AC-1, 2.75-fold for AC-2, and 2.41-fold for AC-3, while no decrease in hTERT expression was detected for MC-1 and MC-2. In the telomere length analysis, reductions of 0.4730-fold for AC-1, 0.076-fold for AC-2, 0.0169-fold for AC-3, 0.289-fold for MC-1, and 0.560-fold for MC-2 were identified. The AC-2 and AC-3 molecules, showing both a reduction in hTERT expression and a decrease in telomere length, suggest that they could be potential candidate agents for the treatment of pancreatic cancer, pending further in vivo research.