Radial shock waves prevent growth retardation caused by the clinically used drug vismodegib in ex vivo cultured bones

Sci Rep. 2020 Aug 7;10(1):13400. doi: 10.1038/s41598-020-69904-0.

Abstract

In childhood medulloblastoma patients, the hedgehog antagonist vismodegib is an effective anti-cancer treatment but unfortunately induces irreversible growth arrests and growth impairment limiting its use in skeletally immature patients. We hypothesized that radial shock wave treatment (rSWT) may protect drug-induced growth impairment owing to its osteogenic effects. Fetal rat metatarsal bones were exposed to vismodegib (day 0-5; 100 nM) and/or rSWT (single session); other bones from day 1 were continuously exposed to a Gli1 antagonist (GANT61; 10 µM) and/or rSWT (single session). Control bones were untreated. The bone length was measured at intervals; histomorphometric analysis and immunostaining for PCNA, Gli1, and Ihh were performed on the sectioned bones. Bones treated with vismodegib showed impaired bone growth, reduced height of the resting-proliferative zone and reduced hypertrophic cell size compared to control. In vismodegib treated bones, a single session of rSWT partially rescued bone growth, increased the growth velocity, hypertrophic cell size, and restored growth plate morphology. Bones exposed to GANT61 showed impaired bone growth and disorganized growth plate while when combined with rSWT these effects were partially prevented. Locally applied rSWT had a chondroprotective effect in rat metatarsal bones and suggest a novel strategy to prevent growth impairment caused by vismodegib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / toxicity*
  • Animals
  • Antineoplastic Agents / toxicity*
  • Bone Development / drug effects*
  • Extracorporeal Shockwave Therapy / methods*
  • Growth Disorders / chemically induced*
  • Growth Disorders / prevention & control*
  • Growth Plate / growth & development
  • Growth Plate / metabolism
  • Hedgehog Proteins / metabolism
  • In Vitro Techniques
  • Metatarsal Bones / embryology
  • Metatarsal Bones / growth & development*
  • Metatarsal Bones / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Pyridines / adverse effects
  • Pyridines / toxicity*
  • Pyrimidines / adverse effects
  • Rats, Sprague-Dawley
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Anilides
  • Antineoplastic Agents
  • GANT 61
  • Gli1 protein, rat
  • Hedgehog Proteins
  • HhAntag691
  • Ihh protein, rat
  • Proliferating Cell Nuclear Antigen
  • Pyridines
  • Pyrimidines
  • Zinc Finger Protein GLI1