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Review
. 2022 Feb 21:13:801733.
doi: 10.3389/fphar.2022.801733. eCollection 2022.

Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies

Rajeev K Singla  1   2 , Sahar Behzad  3   4 , Johra Khan  5   6 , Christos Tsagkaris  7 , Rupesh K Gautam  8 , Rajat Goyal  8 , Hitesh Chopra  9 , Bairong Shen  1
Affiliations
Review

Natural Kinase Inhibitors for the Treatment and Management of Endometrial/Uterine Cancer: Preclinical to Clinical Studies

Rajeev K Singla et al. Front Pharmacol. .

Abstract

Endometrial cancer (EC) is the sixth most prevalent type of cancer among women. Kinases, enzymes mediating the transfer of adenosine triphosphate (ATP) in several signaling pathways, play a significant role in carcinogenesis and cancer cells' survival and proliferation. Cyclin-dependent kinases (CDKs) are involved in EC pathogenesis; therefore, CDK inhibitors (CDKin) have a noteworthy therapeutic potential in this type of cancer, particularly in EC type 1. Natural compounds have been used for decades in the treatment of cancer serving as a source of anticancer bioactive molecules. Many phenolic and non-phenolic natural compounds covering flavonoids, stilbenoids, coumarins, biphenyl compounds, alkaloids, glycosides, terpenes, and terpenoids have shown moderate to high effectiveness against CDKin-mediated carcinogenic signaling pathways (PI3K, ERK1/2, Akt, ATM, mTOR, TP53). Pharmaceutical regimens based on two natural compounds, trabectedin and ixabepilone, have been investigated in humans showing short and midterm efficacy as second-line treatments in phase II clinical trials. The purpose of this review is twofold: the authors first provide an overview of the involvement of kinases and kinase inhibitors in the pathogenesis and treatment of EC and then discuss the existing evidence about natural products' derived kinase inhibitors in the management of the disease and outline relevant future research.

Keywords: endometrial cancer; hormone-sensitive cancer; medicinal plants; metastasis; natural products.

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Conflict of interest statement

Author RS is honorary-based associated with the iGlobal Research and Publishing Foundation (iGRPF), India. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Different types of cells and their function in the EC microenvironment. The microenvironment consists of different components such as myofibroblasts, epithelial cells, and immune cells. (1) TGF-β produced by influx monocytes helps in the conversion of fibroblasts to cancer-associated fibroblasts (CAF). (2) Macrophages induce endometrial carcinogenesis by producing TNF-α, IL-6, and IL-1β that facilitate the conversion of cancer cells to migratory mesenchyme cancer cells. (3) VEGF produced by tumor cells promotes angiogenesis. (4) High-grade EC carries more M2 macrophages, which facilitates more macrophage recruitment via blood vessels.
FIGURE 2
FIGURE 2
Intracellular signaling pathway, including protein kinases and natural products.
FIGURE 3
FIGURE 3
Chemical structures of phytochemicals (Ecteinascidin-743, genistein, and Ixabepilone) used in endometrial cancer in clinical studies.
FIGURE 4
FIGURE 4
Natural products targeted to protein kinase.
See this image and copyright information in PMC

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