Drugs acting on homeostasis: challenging cancer cell adaptation

Abstract

Cancer treatment aims to exploit properties that define malignant cells. In recent years, it has become apparent that malignant cells often survive cancer treatment and ensuing cell stress by switching on auxiliary turnover pathways, changing cellular metabolism and, concomitantly, the gene expression profile. The changed profile impacts the material exchange of cancer cells with affected tissues. Herein, we show that pathways of proteostasis and energy generation regulate common transcription factors. Namely, when one pathway of intracellular turnover is blocked, it triggers alternative turnover mechanisms, which induce transcription factor proteins that control expression of cytokines and regulators of apoptosis, cell division, differentiation, metabolism, and response to hormones. We focus on several alternative turnover mechanisms that can be blocked by drugs already used in clinical practice for the treatment of other non-cancer related diseases. We also discuss paradigms on the challenges posed by cancer cell adaptation mechanisms.

Keywords:

• cell stress
• gene promoter
• homeostasis
• immune system
• metabolism
• signal transduction

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Homeostasis of the entire human organism is the result of heterogeneous interactions between adjacent and distal tissues that regulate differentiation and energy use.

• Cell stress interferes with key regulators of differentiation and endocrine mediators of homeostasis.

• Homeostatic interactions also impact the function of individual cells and affect the fate of malignant cells.

• Importantly, homeostatic interactions can neutralize the effects of antineoplastic agents.

• Proteostasis affects cell fate through multiple mechanisms; induction of protein recycling mechanisms can rescue cancer cells from chemotherapy.

• Homeostasis can be modulated pharmacologically.

• Key factor in the integration of tissue function and containment of tumors is the immune system. Many effective antineoplastic agents are immunosuppressive, while others have a mixed role. Therefore, their use needs to be highly targeted to specific cell types or within a distinct time frame to allow for recovery of essential functions.

• A variety of endocrine and homeostatic responses will be increasingly taken into consideration for the improvement of drug effects.

• The critical issue that arises with most drugs is to target their delivery to reach the concentration threshold needed to impact the niches that host cancer cells, while minimizing side effects on healthy tissue.