Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics

Sci Transl Med. 2019 Jun 19;11(497):eaav1386. doi: 10.1126/scitranslmed.aav1386.


A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Diclofenac / pharmacology
  • Drug Evaluation, Preclinical / methods*
  • Humans
  • Imatinib Mesylate / pharmacology
  • Lab-On-A-Chip Devices
  • Tamoxifen / pharmacology
  • Verapamil / pharmacology


  • Antineoplastic Agents
  • Tamoxifen
  • Diclofenac
  • Imatinib Mesylate
  • Verapamil