Chemotherapy-Mediated Complications of Wound Healing: An Understudied Side Effect

Abstract

Significance: Chemotherapy is a primary method to treat cancer. While chemotherapeutic drugs are designed to target rapidly dividing cancer cells, they can also affect other cell types. In the case of dermal cells and macrophages involved in wound healing, cytotoxicity often leads to the development of chronic wounds. The situation becomes even more severe when chemotherapy is combined with surgical tumor excision. Recent Advances: Despite its significant impact on patients' recovery from surgery, the issue of delayed wound healing in individuals undergoing chemotherapy remains inadequately explored. Critical Issues: This review aims to analyze the harmful impact of chemotherapy on wound healing. The analysis showed that chemotherapy drugs could inhibit cellular metabolism, cell division, and angiogenesis and lead to nerve damage. They impede the migration of cells into the wound and reduce the production of extracellular matrix. At the molecular level, they interfere with replication, transcription, translation, and cell signaling. This work reviews skin problems that patients may experience during and after chemotherapy and demonstrates insights into the cellular and molecular mechanisms of these pathologies. Future Directions: In the future, the problem of impaired wound healing in patients treated with chemotherapy may be addressed by cell therapies like autologous keratinocyte transplantation, which has already proved effective in this case. Epigenetic intervention to mitigate the side effects of chemotherapy is also worth considering, but epigenetic consequences of chemotherapy on skin cells are largely unknown and should be investigated.

The negative impact of medications on wound healing

“…Some intravenous chemotherapy drugs can induce vein irritation which can result in non-healing necrotic ulcers. 1 There are a variety of mechanisms of impaired wound healing due to chemotherapy, such as inhibiting cellular metabolism, cell division or angiogenesis. Many chemotherapeutics disrupt DNA replication, transcription, and translation.…”

“…In wounds they impede cell migration, reduce extracellular matrix production, and inhibit fibroblast proliferation. [1][2][3] Consequences of these mechanisms include apoptosis, cell cycle arrest, senescence, mitotic catastrophe, inflammatory responses and fibrosis. 4 Chemotherapy can severely impair wound healing through profound immunosuppression.…”

“…Furthermore, chemotherapy has been shown to impair multiple stem cell types in skin including mesenchymal stromal stem cells (MSCs), epidermal stem cells (EPSCs), and hair follicle stem cells (HFSCs). 1,9,10 Vesicants Some chemotherapy drugs are vesicants which when extravasated can inflict permanent tissue damage. Symptoms of vesicant extravasation include erythema and pain that can progress to blistering, desquamation, necrosis, eschar formation and ulceration.…”

“…15 Chemotherapy affecting growth factors and angiogenesis Chemotherapy blocks the synthesis of growth factors subsequently causing decreased cell migration, decreased proliferation and reduced angiogenesis. 1 Capecitabine and oxaliplatin have been shown to cause reduction in measured levels of growth factors including epidermal growth factor (EGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). 16 These growth factors are important for angiogenesis, hence, the anti-angiogenic properties of chemotherapy may be a key cause for impaired wound healing in these patients.…”

“…16 These growth factors are important for angiogenesis, hence, the anti-angiogenic properties of chemotherapy may be a key cause for impaired wound healing in these patients. 1 VEGF plays multiple roles in wound healing: recruitment of monocytes, macrophages, fibroblasts and endothelial cells, increased vascular permeability, and deposition of collagen. 17 The monoclonal antibody VEGF inhibitor bevacizumab works as a treatment for colon cancers by inhibiting new vessel formation, altering vascular function and decreasing tumour blood flow.…”