Secondary Metabolites from Croton Species and Their Biological Activity on Cell Cycle Regulators

Abstract

Plant-based traditional medicine integrates beliefs, knowledge, and practices to prevent and treat multiple diseases. Croton is a large and worldwide-spread genus belonging to Euphorbiaceae, a family well known for comprising many species with medicinal properties due to its high diversity of phytochemical constituents with biological activities. Among the various benefits of Croton species in traditional medicine, its use in cancer treatment has recently received significant attention from the scientific community. This review provides a general overview of different studies on the Croton genus in the research for alternative cancer treatments and the impact of its secondary metabolite catalog on cell cycle targets. Our analysis indicates that just under 30 secondary metabolites have been identified so far in latex and extracts obtained from leaves, twigs, or bark from 22 different Croton species. Based on standard assays using cell lines or human platelets, these molecules show multiple biological activities mainly compromising cell viability and cell cycle progression, supporting the ethnobotanical use of Croton species for cancer treatment. Several studies indicate that Croton metabolites target CDK-cyclin complexes and signaling routes that trigger apoptosis; however, further studies are needed to better understand the molecular mechanisms underlying Croton metabolites' effects and their accurate future applications in cancer treatment.

Keywords: apoptosis; cancer; cell cycle; plant metabolites; tropical plant species.

Figure 1

Some Croton species with ethnopharmacological studies associated with cell cycle regulators. (A) C. draco Schltdl var. draco tree growing in Mexico. In this species, secondary metabolite-rich latex can be extracted from (B) branches and (C) stems. (D) Sectional classification of Croton species with applications in cancer treatment.

Figure 2

Traditional uses of and patents for Croton species worldwide. (A) Geographical distribution of scientific publications detailing ethnopharmacological applications by country. (B) Summary of cancer cell lines reported in Croton antiproliferative assays. (C) Patents protecting biotechnological and pharmacological uses of Croton species reported in the last 61 years. Diagrams created with BioRender.

Figure 3

Chemical structures of SMs with reported cell cycle-related targets that have been identified in Croton species: (1) Trans-dehidrocrotonin, (2) Trans-crotonin, (3) Ent-trachyloban-3,-ol, (4) Crotonquinin A, (5) Crotonquinin B, (6–9) Furanocembranoids 1-4, (10) Catechin, (11) Galocatechin, (12) Ascaridol, (13) Taspine, (14–16) Ent-kaurene 1-3, (17) Rutin, (18) Vitexin, (19) Crourorb A1, (20) Crotobarin, (21) Crotogoudin, (22) B10G5, (23) Plaunotol, (24) Ent-kaurane I, (25) NCKU_PCKuo_0001, and (26) Chettaphanin II.

Figure 4

Schematic representation of cell cycle control by natural compounds from the Croton genus. Progression through the cell cycle involves the formation, activation, and successive participation of cyclin-dependent protein kinases (CDKs), which bind sequentially to a series of cyclins and regulate the cell cycle at different stages. Crude extracts and natural compounds isolated from the Croton genus, e.g., taspine, plaunotol, B10G5, chettaphanin II, NCKU_PCK_000, and ent-kaurane-I, have been shown to influence specific targets at different points, altering cell cycle progression through inhibition of CDK–cyclin complexes and overexpression of apoptosis mediators. In addition to cell cycle arrest induction, upstream signaling routes that sense DNA damage and trigger cell death programs via gene expression modulation have also been linked to Croton extracts such as CCEO, CTEO, TPD7, and crourorbA1. Diagram created with BioRender.