3D Cell Cultures Improve Drug Screening Accuracy but Show Lower Efficacy for Anti-Cancer Drugs

Three-dimensional (3D), spheroid-based cell cultures have been a significant improvement over monolayer cell cultures in offering more accurate models of clinical scenarios for drug screening. However, although the cellular environment is mimicked more accurately in 3D models, the efficacy of potential anti-cancer drugs in 3D cultures is often lower than that in monolayer cell cultures.

In a recent review published in Drugs and Drug Candidates, researchers from Brazil examined the existing knowledge on monolayers and spheroid-based cell cultures, including the constituent compounds, and the difference in efficacy during drug screening, especially for anti-cancer drugs targeting cytoskeletal dynamics and cell cycles.

​​​​​​​Study: Two-Dimensional and Spheroid-Based Three-Dimensional Cell Culture Systems: Implications for Drug Discovery in Cancer. Image Credit: paulista/Shuttertsock.com​​​​​​​Study: Two-Dimensional and Spheroid-Based Three-Dimensional Cell Culture Systems: Implications for Drug Discovery in Cancer. Image Credit: paulista/Shuttertsock.com

Background

The development of monolayer cell culture technology has radically changed the nature and scope of various biological research domains.

What began with Ross G. Harrison culturing live embryonic frog nerve fibers was advanced with the invention of the Carrel flask and Eagle’s culture media, which helped grow and maintain various types of cell lines.

Monolayer cultures have significantly improved our understanding of cellular processes, especially tumor biology, and provided a suitable and effective platform for testing chemotherapeutic drugs.

However, the in vivo cellular landscape presents various hurdles to drug delivery, such as various cytoskeletal structures, adhesion complexes, and interactions with the stroma that alter the drug's diffusion.

Spheroid-based 3D cell cultures mimic the nutrient gradients in the cellular environment more accurately, providing a suitable platform for testing anti-cancer drugs.

Cell-cycle and Cytoskeleton Targeting Drugs in 3D Cell Cultures

Spheroid-based cultures have an outer proliferative region that has high oxygen concentration and is rich in nutrients. The layer that follows contains quiescent cells, and the center is comprised largely of necrotic cell clusters.

A nutrient gradient forms towards the center, with the inner layers containing accumulated carbon dioxide and cell debris and lower concentrations of nutrients and oxygen.

This nutrient gradient also shields the inner layers from the effects of drugs, as observed when testing anti-cancer drugs such as temozolomide on glioblastoma cell lines.

The increase in intercellular adhesion in spheroid cell cultures was shown to lower the efficacy of anthracyclines such as 5-fluorouracil and chemotherapeutics such as romidepsin, docetaxel, oxaliplatin, and binimetinib.

However, some drugs have been found to be effective in penetrating the 3D structure of spheroid cell cultures and bringing about changes in the cell cycle. These include olaparib and vincristine in breast and ovarian cancer cell lines.

Drugs such as imatinib were found to reduce intercellular interactions, inducing mitochondrial damage and apoptosis in spheroids. Tamoxifen was also observed to lower the migration and cell clustering rates in breast cancer spheroid cell cultures, lowering the cancer cells' metastatic potential.

Given that the cytoskeletal structure is vital to cell communication and cellular migration, drug development research is also focusing on anti-neoplastic drugs that can disrupt the cytoskeleton and those targeting the actin microfilaments to prevent cell migration.

Drugs that destabilize the cytoskeleton include geodiamolides that disrupt actin filaments and actin polymerization inhibitors such as latrunculin and cytochalasin.

Doxorubicin, a chemotherapeutic drug, can disrupt cytoskeleton dynamics. Doxorubicin nanoparticles formed using lactic-co-glycolic acid and curcumin have been found to inhibit breast cancer cell lines.

The folic acid antimetabolite methotrexate has also been found to shrink cervical cancer cells in monolayer cultures.

Tyrosine kinase inhibitors are another class of drugs used to limit the invasion and spread of cancer cells. Studies have proven the efficacy of imatinib, a tyrosine kinase inhibitor, in improving outcomes in patients with chronic myeloid leukemia.

Additionally, epidermal growth factor receptors such as gefitinib, erlotinib, and osimertinib have been observed to interfere with cytoskeletal structure and have been used to treat non-small-cell lung cancers.

The review also discussed various other classes of potential cancer drugs, such as histone deacetylase inhibitors that impact the cytoskeletal structure and their efficacies in monolayer and spheroid cell cultures.

Drug Screening in Spheroid Cell Cultures

The study stated that since differences in cell culture methods might influence the drug response, maintaining the homogeneity of the 3D cell cultures and standardizing the process was essential for the drug testing results to be reliable.

Co-cultures were found to be a useful bioengineering approach for studying cancer progression and testing potential chemotherapeutic drugs. They mimicked the cancer environment and provided a more accurate model for studying cancer cell interactions and drug testing.

The researchers also reported that the more accurate simulation of complex diseases such as cancer using 3D cell cultures is resulting in a shift in drug research, with pharmaceutical companies and the Food and Drug Administration preferring 3D cell cultures over animal models for drug testing.

Conclusions

Overall, the review presented a comprehensive summary of the current state of 3D cell culture research and the gradual shift in drug testing and cancer research from monolayer cell cultures to spheroid cell cultures that more accurately mimic the cancer environment.

The researchers also discussed in detail the current classes of chemotherapeutic drugs used to disrupt cell-cycle processes and the cytoskeletal structure and their efficacies in monolayer and spheroid cell cultures.

Journal reference:

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