Intracellular Mechanical Drugs Induce Cell‐Cycle Altering and Cell Death

Abstract

physical terms, the combination of cell membrane-cortex system and cytoskeleton constitutes a mechanical system whose stability is based on a force balance between compression and tensileload-bearing components. [1] Any physical perturbation of this cellular mechanical system elicits a redistribution of forces and rearrangement of mechanical elements that can be disruptive. [3] Thus, it is not surprising that multiple chemical drugs for research and therapeutics target to alter the cellular mechanical performance. Anticancer drugs such as paclitaxel or colchicine affect the microtubules, provoking mitotic catastrophe to cause cell death. [4,5] Other compounds, including cytochalasin B, cytochalasin D, and latrunculin A disrupt actin filaments, also disturbing cell function and growth. [6] Intracellular mechanical cues induced by physiological internalization of large objects can also alter the redistribution of forces and the rearrangement of mechanical elements. Indeed, during entosis (the engulfment of one living cell by another), cytokinesis in the engulfing cell is perturbed, which can cause aneuploidy. [7,8] This has parallels to cell division perturbation when cells are exposed to natural or artificial "long" fibrous material such as asbestos fibers that can induce genomic changes and cancer by sterically blocking cytokinesis. [9] Current advances in materials science have demonstrated that extracellular mechanical cues can define cell function and cell fate. However, a fundamental understanding of the manner in which intracellular mechanical cues affect cell mechanics remains elusive. How intracellular mechanical hindrance, reinforcement, and supports interfere with the cell cycle and promote cell death is described here. Reproducible devices with highly controlled size, shape, and with a broad range of stiffness are internalized in HeLa cells. Once inside, they induce characteristic cell-cycle deviations and promote cell death. Device shape and stiffness are the dominant determinants of mechanical impairment. Device structural support to the cell membrane and centering during mitosis maximize their effects, preventing spindle centering, and correct chromosome alignment. Nanodevices reveal that the spindle generates forces larger than 114 nN which overcomes intracellular confinement by relocating the device to a less damaging position. By using intracellular mechanical drugs, this work provides a foundation to defining the role of intracellular constraints on cell function and fate, with relevance to fundamental cell mechanics and nanomedicine.