Dataset Information

The different biological effects of TMPyP4 and cisplatin in the inflammatory microenvironment of osteosarcoma are attributed to G-quadruplex.

ABSTRACT:

Objective

Osteosarcoma (OS) is characterized by high levels of the tumour-associated inflammatory microenvironment. Moreover, in approximately 60% of OS, telomere length is maintained by alternative lengthening of telomeres (ALT) pathway. Whether the ALT pathway can be exploited for OS therapeutic treatment and how the OS inflammatory microenvironment influences the anti-cancer drug effect remains unknown. Here, we examined the biological effects of TMPyP4 and cisplatin in the inflammatory microenvironment of OS cells.

Materials and methods

Immunofluorescence in situ hybridization (IF-FISH) and C-circle experiments were used to detect the G-quadruplex and ALT activity. The redox potential of single guanine, G-quadruplex and G-quadruplex/TMPyP4 was evaluated by the lowest unoccupied molecular orbital energy (LUMO), zeta potential and cyclic voltammetry. Cell viability, flow cytometry and apoptosis, Western blot, comet assay, adhesion, transwell and scratch experiments were performed to compare the anti-tumour proliferation and migration effects of TMPyP4 and cisplatin in the inflammatory microenvironment.

Results

This study indicated that compared with cisplatin, TMPyP4 could induce the formation of human telomeres and FAK G-quadruplex in vitro and in vivo, and TMPyP4-treated OS cells showed fewer extrachromosomal C-circles and fewer ALT-associated promyelocytic leukaemia bodies. Consequently, the ALT activity and FAK-related cell migration were suppressed by TMPyP4. Mechanistically, the formation of G-quadruplex resulted in both lower redox potential than G within the genome and FAK transcription inhibition, and TMPyP4 could enhance this phenomenon, especially in the inflammatory microenvironment.

Conclusions

Our results reveal that TMPyP4 is more suitable for OS treatment than cisplatin.

SUBMITTER: Chen J

PROVIDER: S-EPMC8450119 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundWhile multiagent chemotherapy has dramatically improved the prognosis of sarcoma, the novel chemotherapeutics have hardly developed over the past 30 years. Caffeine can induce apoptosis, delays in cell cycle progression and can enhance the cytocidal effects of anti-cancer agents. Citrate has been reported to enhance the cytocidal effect of cisplatin in gastric cancer in vitro. However its effect in sarcoma cells had not been reported.MethodsThis study was designed to evaluate whether the addition of caffeine, citrate, or caffeine citrate to cisplatin improved its cytocidal effect (cell survival, proliferation, and apoptosis) on human osteosarcoma (HOS), human fibrosarcoma (HT1080) and murine osteosarcoma (LM8) cell lines. We also tested the various combinations in a mouse heterotopic transplantation model in vivo. In cell survival assay, combination index (CI) of caffeine citrate was calculated as a combination of anhydrous caffeine and citric acid, and the synergy was evaluated (CI < 1.0).ResultsIn all cell lines, cisplatin combined with caffeine citrate significantly reinforced the anticancer effect compared with cisplatin alone, combination of cisplatin and anhydrous caffeine, and combination of cisplatin and citric acid. Moreover, CI was < 1.0 in all conditions. The anticancer agent reinforcement effect of caffeine citrate was synergy of anhydrous caffeine and citric acid. In cell proliferation and cell cycle assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in inducing G0/G1 cell-cycle arrest with subsequent suppressed cell proliferation. In mitochondrial depolarization and caspase 3/7 activity assay revealed that caffeine citrate had most strong effect as a combination drug than caffeine and citric acid in apoptosis associated with decreased mitochondrial membrane potential. In vivo, three different drug concentrations were tested, and cisplatin combined with caffeine citrate was found to have the strongest antitumor effect.ConclusionsThis is the first report demonstrating that caffeine citrate has a significantly greater potentiating effect on cisplatin than adding either caffeine or citric acid. The combination of cisplatin with caffeine citrate is a novel treatment that might hold promise for improving the outcome of osteosarcoma and fibrosarcoma, which up till now has generally not responded well to chemotherapy.