Zoledronic acid targets chemo-resistant polyploid giant cancer cells

Abstract

Although polyploid giant cancer cells (PGCCs) are known as a key source of failure of current therapies, sufficient drugs to target these cells are not yet introduced. Considering the similarities of polyploid cells in regeneration and cancer, we hypothesized that zoledronic acid (ZA), an osteoclast-targeting agent, might be used to eliminate PGCCs. The 5637-bladder cancer cell line was treated with various doses of cisplatin to enrich polyploid cells and the efficacy of different concentrations of ZA in reducing this population was assessed. The metabolic profile of PGCCs was investigated with gas chromatography-mass spectrometry. Lipid profiles, mitochondrial density, and ROS content were also measured to assess the response of the cells to ZA. Cancer cells surviving after three days of exposure with 6 μM cisplatin were mainly polyploid. These cells demonstrated special morphological features such as fusion with diploid or other polyploid cells and originated in daughter cells through budding. ZA could substantially eradicate PGCCs with the maximal effect observed with 50 μM which resulted in the drop of PGCC fraction from 60 ± 7.5 to 19 ± 1.7%. Enriched PGCCs after cisplatin-treatment demonstrated a drastic metabolic shift compared to untreated cancer cells with an augmentation of lipids. Further assays confirmed the high content of lipid droplets and cholesterol in these cells which were reduced after ZA administration. Additionally, the mitochondrial density and ROS increased in PGCCs both of which declined in response to ZA. Taken together, we propose that ZA is a potent inhibitor of PGCCs which alters the metabolism of PGCCs. Although this drug has been successfully exploited as adjuvant therapy for some malignancies, the current evidence on its effects on PGCCs justifies further trials to assess its potency for improving the success of current therapies for tackling tumor resistance and relapse.

Increased [18F]FDG uptake of radiation-induced giant cells: a single-cell study in lung cancer models

“…Beyond radiation therapy, multinucleated giant cells implicated in diseases like schistosomiasis, sarcoidosis, and arthritis require substantial energy for their formation, especially for membrane fusion and cytoplasmic expansion, thereby necessitating increased glucose uptake 19 . Additionally, chemotherapy-induced polyploid giant cancer cells undergo significant metabolic shifts post-treatment, indicating altered metabolic pathways, including those related to glucose metabolism 20 . These insights highlight the broader metabolic requirements of giant cells, underscoring their adaptive responses to diverse stressors.…”

Regenerative potential of multinucleated cells: bone marrow adiponectin-positive multinucleated cells take the lead

“…In a recent review, we proposed an analogy between the function of polyploid cells in cancer and regeneration [ 29 ]. In line with this concept, we found zoledronic acid that is an osteoclast targeting agent to be effective in eradicating PGCCs originated from bladder cancer cells [ 34 ].…”

Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis

“…155 PGCCs are rich in mitochondria, which support the survival of cancer cells by producing ATP. Adibi et al 156 reported increased lipid droplet formation has been observed in PGCCs. Lipids likely serve as energy stores that help PGCCs endure stress.…”

“…This indicates that targeting lipid metabolism in PGCCs may represent a promising strategy for overcoming chemoresistance and improving the success rate of cancer treatment. 156 (4) Induced-differentiation. PGCCs cultured in medium containing 3-isobutyl-1-methylxanthine, insulin, dexamethasone and rosiglitazone can be induced to transdifferentiate into mature functional adipocytes.…”

“…ZA significantly reduced lipid droplets and cholesterol levels in PGCCs. This indicates that targeting lipid metabolism in PGCCs may represent a promising strategy for overcoming chemoresistance and improving the success rate of cancer treatment 156 . (4) Induced‐differentiation.…”