Quantifying cell cycle-dependent drug sensitivities in cancer using a high throughput synchronisation and screening approach

Abstract

Background: Chemotherapy and targeted agent anti-cancer efficacy is largely dependent on the proliferative state of tumours, as exemplified by agents that target DNA synthesis/replication or mitosis. As a result, cell cycle specificities of a number of cancer drugs are well known. However, they are yet to be described in a quantifiable manner. Methods: A scalable cell synchronisation protocol used to screen a library of 235 anti-cancer compounds exposed over six hours in G1 or S/G2 accumulated AsPC-1 cells to generate a cell cycle specificity (CCS) score. Findings: The synchronisation method was associated with reduced method-related cytotoxicity compared to nocodazole, delivering sufficient cell cycle purity and cell numbers to run high-throughput drug library screens. Compounds were identified with G1 and S/G2-associated specificities that, overall, functionally matched with a compound's target/mechanism of action. This annotation was used to describe a synergistic schedule using the CDK4/6 inhibitor, palbociclib, prior to gemcitabine/AZD6738 as well as describe the correlation between the CCS score and published synergistic/antagonistic drug schedules. Interpretation: This is the first highly quantitative description of cell cycle-dependent drug sensitivities that utilised a tractable and tolerated method with potential uses outside the present study. Drug treatments such as those shown to be G1 or S/G2 associated may benefit from scheduling considerations such as after CDK4/6 inhibitors and being first in drug sequences respectively.

Model design choices impact biological insight: Unpacking the broad landscape of spatial-temporal model development decisions

“…We compare emergent metrics from simulations of cells that start at the same volume and simulations of cells with initial volumes drawn from a normal distribution. Cell cycle synchronization enables researchers to study cell cycle regulation and control, while asynchronous populations reflect unperturbed growth [ 15 , 16 ]. Cell age captures the initial distribution of cell ages, which is relevant to division history, accumulation of mutations, and self-renewal.…”

Tubulin beta 4B chain is involved in the cell cycle process of mouse spermatogonia through CDK2

“…Under the in uence of drugs such as colchicine, griseofulvin, and nocodazole, microtubule formation is inhibited in mouse zygotes, the process of mitosis cannot be initiated, and the embryos cease to develop [42] . On the other hand, nocodazole and its complexes are less toxic to cells and are often used to study the G2-M phase synchronization of the cell cycle [25,[43][44] . Nocodazole is a tubulin polymerization inhibitor that blocks cell cycle progression by preventing spindle formation [24,26,45] .…”

Magnetomechanical Stress-Induced Colon Cancer Cell Growth Inhibition

“…Many chemotherapeutic agents such as platinum-based compounds and cyclin-dependent kinases (CDKs) inhibitors that induce cell cycle arrest, have been shown to antagonistically interact with paclitaxel's activity in combination chemotherapy schemes, when given prior to or simultaneously with paclitaxel. On the same basis, various levels of synergy have been reported for many combinations of cell-cycle-specific drugs [42][43][44]. The sequence dependency of such interactions between antitumor drugs combined with agents that exert cell-cycle-specific activities may be considered so that synergistic effects can be achieved.…”

“…Thus, there is a recently renewed interest in the discovery of novel CDK inhibitors, while pharmacologic inhibitors of CDKs 4 and 6 specifically have changed the treatment landscape for breast cancer [45][46][47][48][49]. In certain cases though, low therapeutic indexes, mixed cellular responses, and unexpected effects have been reported due to the diverse impact the inhibitors have in cells [42,48,50,51]. Therefore, the cytostatic effect exerted by the 200 mT static magnetic-field-actuated MNPs in HT29 cells is an important observation that could be further explored aiming at the development of novel anticancer combination therapies.…”