It is well known that a decreased expression or inhibited activity of telomerase in cancer cells is accompanied by an increased sensitivity to some drugs (e.g., doxorubicin, cisplatin, or 5-fluorouracil). However, the mechanism of the resistance resulting from telomerase alteration remains elusive. There are theories claiming that it might be associated with telomere shortening, genome instability, hTERT translocation, mitochondria functioning modulation, or even alterations in ABC family gene expression. However, association of those mechanisms, i.e., drug resistance and telomerase alterations, is not fully understood yet. We review the current theories on the aspect of the role of telomerase in cancer cells resistance to therapy. We believe that revealing/unravelling this correlation might significantly contribute to an increased efficiency of cancer cells elimination, especially the most difficult ones, i.e., drug resistant.

Telomerase is perceived as an immortality enzyme that enables passing the Hayflick limit. Its main function is telomere restoration but only in a limited group of cells, including cancer cells. Since it is found in a vast majority of cancer cells, it became a natural target for cancer therapy. However, it has much more functions than just altering the metabolism of telomeres—it also reveals numerous so-called non-canonical functions. Thus, a question arises whether it is always beneficial to turn it off when planning a cancer strategy and considering potential side effects? The purpose of this review is to discuss some of the recent discoveries about telomere-independent functions of telomerase in the context of cancer therapy and potential side effects.

Proper functioning of cells—their ability to divide, differentiate, and regenerate—is dictated by genomic stability. The main factors contributing to this stability are the telomeric ends that cap chromosomes. Telomere biology and telomerase activity have been of interest to scientists in various medical science fields for years, including the study of both cancer and of senescence and aging. All these processes are accompanied by telomere-length modulation. Maintaining the key levels of telomerase component (hTERT) expression and telomerase activity that provide optimal telomere length as well as some nontelomeric functions represents a promising step in advanced anti-aging strategies, especially in dermocosmetics. Some known naturally derived compounds contribute significantly to telomere and telomerase metabolism. However, before they can be safely used, it is necessary to assess their mechanisms of action and potential side effects. This paper focuses on the metabolic potential of natural compounds to modulate telomerase and telomere biology and thus prevent senescence and skin aging.

Human telomeres were one of the first discovered and characterized sequences forming quadruplex structures. Association of these structures with oncogenic and tumor suppressor proteins suggests their important role in cancer development and therapy efficacy. Since cationic porphyrin TMPyP4 is known as G-quadruplex stabilizer and telomerase inhibitor, the aim of the study was to analyze the anticancer properties of this compound in two different human breast-cancer MCF7 and MDA-MB-231 cell lines. The cytotoxicity of TMPyP4 alone or in combination with doxorubicin was measured by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromid) and clonogenic assays, and the cell-cycle alterations were analyzed by flow cytometry. Telomerase expression and activity were evaluated using qPCR and telomeric repeat amplification protocol (TRAP) assays, respectively. The contribution of G-quadruplex inhibitor to protein pathways engaged in cell survival, DNA repair, adhesion, and migration was performed using immunodetection. Scratch assay and functional assessment of migration and cell adhesion were also performed. Consequently, it was revealed that in the short term, TMPyP4 neither revealed cytotoxic effect nor sensitized MCF7 and MDA-MB-231 to doxorubicin, but altered breast-cancer cell adhesion and migration. It suggests that TMPyP4 might substantially contribute to a significant decrease in cancer cell dissemination and, consequently, cancer cell survival reduction. Importantly, this effect might not be associated with telomeres or telomerase.