Usefulness of Natural Phenolic Compounds in the Fight against Esophageal Cancer: A Systematic Review

Abstract

Esophageal cancer (EC) is a very common form of cancer in developing countries, and its exponential progression is a cause for concern. Available treatments face the phenomenon of multi-drug resistance, as well as multiple disabling side effects. The number of deaths is expected to double by 2030 if nothing is done. Due to their high representativeness in plants, phenolic compounds are a potential alternative for halting the spread of this disease, which bereaves many thousands of families every year. This study aims to identify phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and explore future perspectives. To achieve this, the literature search was meticulously carried out in the Google Scholar, Scopus, Web of Sciences, and Pub-Med/Medline databases, in accordance with the PRISMA 2020 guidelines. The results show that proanthocyanidin and curcumin represent promising therapeutic options, given their significant in vitro and in vivo activity, and their safety in human subjects in clinical trials. Moscatilin, Genistein, and pristimerin have anticancer activities (≤10 µM) very close to those of doxorubicin and 5-FU, although their safety has not yet been fully established. The compounds identified in vivo exhibit highly significant activities compared with the results obtained in vitro, and are sometimes more effective than the molecules conventionally used to treat EC. Generally, with the exceptions of plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a therapeutic avenue to be explored by pharmaceutical companies in the fight against esophageal cancer. However, more detailed toxicological studies of certain molecules remain a priority.

1. Introduction

People have always used medicinal plants to prevent and treat diseases. These plants possess a multitude of secondary metabolites that, alone or in combination, provide an undeniable therapeutic alternative to current health problems [1]. This is justified by the fact that over 25% of marketed medicines are derived from plants [2]. Among the active constituents of plants, the group of phenolic compounds occupies a prominent place [3]. They are produced in plants by metabolizing phenylpropanoids (shikimic acid and pentose phosphate) [4]. Their spectrum encompasses basic phenolic molecules to extensively polymerized compounds, all having benzene rings with one or more hydroxyl substituents [5]. This group contains numerous families of compounds: flavonoids, phenolic acids, tannins, stilbenes, coumarins, anthocyanins, and lignans [6,7]. Phenolic compounds play a crucial role in plant protection by defending against pathogens and environmental stressors, such as UV radiation and drought [8]. They also contribute to plant growth regulation and defense against herbivores through their repellent and toxic properties [9]. Additionally, certain phenolic compounds attract pollinators, thus facilitating plant reproduction [10]. They are also responsible for a wide range of biological activities in human health, including anti-inflammatory, anticancer, anti-aging, antioxidant, antibacterial, antiviral activities, cardiovascular protection, and cognitive health enhancement [11,12,13].

Regarding anti-cancer activity, numerous studies have reported notable biological effects of various phenolic compounds against specific cancer types, including esophageal cancer. EC is a significant health issue due to its rising incidence and high mortality rate, with approximately 604,100 new cases and 544,076 deaths globally each year [14,15]. Its exponential progression raises concern, as the number of deaths is expected to double by 2030 according to GLOBOCAM forecasts if no action is taken [14]. Two main types of esophageal cancer have been identified: esophageal adenocarcinoma (EAC), which is prevalent in high-income countries, and esophageal squamous cell carcinoma (ESCC), a highly aggressive form that is more commonly found in developing countries. The disease is particularly troubling because of its various risk factors, including excessive alcohol consumption, smoking, and gastroesophageal reflux disease [14]. The challenge of treating esophageal cancer is heightened by the fact that many patients are diagnosed at advanced stages, which severely limits treatment options and impacts survival rates [16]. The situation is further complicated by the development of drug resistance and severe side effects associated with current treatments, leading to poor patient adherence [1]. Despite some studies showing promising in vitro and in vivo activities of certain phenolic compounds against esophageal cancer, no effective therapeutic products have yet been developed. This review aims to compile a comprehensive summary of natural phenolic compounds with activity against esophageal cancer, assess their toxicological profiles, and provide insights into future research directions. By exploring these compounds, we seek to identify potential avenues for enhancing the treatment of this challenging disease and guiding pharmaceutical development.

2. Methodology

2.1. Data Sources, Search Strategy, and Eligibility Criteria

Original works published before July 2024 were collected in Google Scholar, Scopus, Web of Science, and Medline/PubMed databases and methodically appraised according to the PRISMA 2020 guidelines (see Supplementary File S1) [17]. The search terms included “anti-esophageal cancer” OR “anti-esophageal squamous-cell carcinoma”; OR “anti-esophageal adenocarcinoma” AND “phenolic compounds” AND “biological activity” OR “pharmacological activity”. Studies were included if they evaluated the anti-esophageal cancer activity of compounds belonging to the phenolic compounds group as a primary or secondary objective. Only original published studies were included. Studies focusing on other metabolite groups were excluded from this work. Review articles, conference abstracts, and editorials were also excluded. No restrictions regarding language or date were applied to this study.

2.2. Selection Process and Data Collection

To improve the organization of the selection and review process, the search results were first exported to Endnote for duplicate removal and then transferred to the Rayyan program [18]. The authors (EJN, GTK) independently screened the titles and abstracts. Subsequently, a second independent selection was conducted by reviewing the full texts of the articles retained after the first review. Any disagreements were resolved through discussion. Data such as phenolic compounds, structure, extracted plants, and biological properties were extracted from the various studies. For biological properties, study results (IC₅₀, therapeutic doses, etc.) were independently extracted from the studies by the authors.

2.3. Synthesis Methods

The process of synthesizing and analyzing data was methodical. It started with a general summary of the studies and then classified them to achieve a more in-depth understanding. A detailed summary table was created to provide an effective visual representation of the key findings from the included studies. Then, a narrative synthesis will be conducted, given that this is a systematic review [1].

3. Results

3.1. Search Outcomes and Studies Characteristics

The research process (see Figure 1) yielded 30 studies and 25 compounds belonging to the following groups: chalcones (Moscatilin, Isoliquiritigenin, and 3-deoxysappanchalcone); Coumarins (Osthole); polyphenolic-flavonoids (Quercetin, Icariin, Purpurogallin, 6,7,4′-Trihydroxyisoflavone, Genistein, Hesperetin, Baohuoside-I, Curcumin, 2,6-Bis Benzylidine cyclohexanone, Proanthocyanidin, Gallic acid, theaflavin-3-3′-digallate, (-)-epigallocatechin-3-gallate, Theaflavate A, and Sesamin); quinones (Lapachol, β-lapachone, Pristimerin, Plumbagin); tannin (Corilagin); xanthone (Griffipavixanthone). The studies originated from three (3) continents: Africa, Asia, and America. Asia accounts for the largest number of studies, with 19 from China, 2 each from Taiwan, the Republic of Korea, and Japan, and 1 from Iran (See

Table 1. Description of included studies.

Class	Number	Compounds	Structure	Plants of Origin	Cancer Lines	References (Country)
Chalcone	1	Moscatilin		Stem of Dendrobium loddigesii	ESCC cells (CE81T/VGH) EAC cells (BE3)	(Taiwan) [19]
					ESCC cells (CE81T/VGH)	(Taiwan) [21]
	2	Isoliquiritigenin		Licorice root or Glycyrrhiza glabra	ESCC cells (KYSE140, KYSE520, TE-1)	(China) [22]
	3	3-deoxysappanchalcone (3-DSC)		Caesalpinia sappan L.	ESCC cells (KYSE 70, KYSE 30, KYSE 410, KYSE 510, KYSE 450)	(Republic of Korea) [23]
Coumarin	4	Osthole		Fruit of Fructus cnidii	ESCC cells (KYSE30, KYSE150, KYSE180, KYSE410, KYSE450)	(China) [24]
Polyphenolic Flavonoid	5	Quercetin		Foods (grapes, onions, berries, broccoli, cherries, and citrus fruits)	ESCC Eca-109 cells	(China) [25]
	6	Icariin		Epimedium spp.	ESCC KYSE70 cell	(China) [26]
					ESCC cells (Eca109, TE-1)	(China) [27]
	7	Purpurogallin		Nutgalls and oak bark of Quercus spp	ESCC cells (KYSE70, KYSE30, KYSE410, KYSE450, KYSE510)	(China) [28]
					ESCC KYSE510 cells	(USA) [29]
	8	(6,7,4′-THIF) or 6,7,4′-Trihydroxyisoflavone		Glycine max L. Merr. (Soybean)	ESCC cells (KYSE 30, KYSE 450, KYSE 510)	(Republic of Korea) [30]
	9	Genistein		Glycine max L. Merr. (Soybean)	ESCC cells (EC9706, Eca-109, CaES-17, Het-1A)	(China) [31]
	10	Hesperetin		Lemons and oranges	ESCC Eca-109 cells	(China) [32,33]
	11	Baohuoside-I		Cortex periplocae	ESCC Eca-109 cells	(China) [34]
	12	Curcumin		Curcuma longa	ESCC cells (T.Tn, TE-1, TE-6, TE-5, TE-8, TE-11, TE-10, TE-11R, HCE-4)	(Japan) [35]
					ESCC cells (KYSE30)	(Iran) [36]
					ESCC cells (TE-1, TE-8, KY-5, KY-10, YES-1, YES-2)	(USA) [37]
	13	2,6-Bis Benzylideno cyclohexanone		Curcumin analogues	ESCC cells (KYSE30)	(Iran) [36]
	14	Proanthocyanidins		Vitis vinifera L. (Grape seeds)	ESCC Eca-109 cells	(China) [38]
				Cranberry	EAC cells (OE19, JHAD1, OE33)	(USA) [20]
	15	Gallic acid		Phaleria macrocarpa (Scheff.)	ESCC TE-2 cells	(Japan) [39]
	16	Sesamin		Sesamum indicum	ESCC cells (KYSE150, EC9706, Eca-109, TE-2)	(China) [40]
	17	(-)-epigallocatechin-3-gallate		Green tea of Camellia sinensis L.	ESCC cells (Eca-109, KYSE 510)	(China) [41] (USA) [29]
	18	Theaflavin-3-3′-digallate		Black tea of Camellia sinensis L.	ESCC cells (Eca-109, KYSE 510)	(China) [41] (USA) [29]
	19	Theaflavate A			ESCC KYSE 510 cells	(USA) [29]
Quinones	20	Lapachol		Tabebuia avellanedae	ESCC WHCO1 cells	(South Africa) [42]
					ESCC cells (KYSE30, KYSE450, KYSE510)	(China) [43]
	21	β-lapachone		Tabebuia avellanedae	ESCC WHCO1 cells	(South Africa) [42]
	22	Pristimerin		Celastraceous and Hippocratic	ESCC Eca-109 cells	(China) [44]
					ESCC cells (EC9706, Eca-109, KYSE3)	(China) [45]
	23	Plumbagin		Plumbago zeylanica L.	ESCC cells (KYSE150, KYSE450)	(China) [46]
Tannin	24	Corilagin		Phyllanthus emblica L.	ESCC cells (ECA109, KYSE150)	(China) [47]
Xanthone	25	Griffipavixanthone		Garcinia esculenta	ESCC cells (TE-1, KYSE150)	(China) [48]

Legend: EAC = Esophageal Adenocarcinoma; ESCC = Esophageal Squamous Cell Carcinoma.

). On the American continent, only the USA is represented with 3 studies. In Africa, South Africa is the only country represented with 1 study. Although the majority of studies reported the activities of compounds against the ESCC variant, two studies investigated the activities of Moscatilin and Proanthocyanidins against the EAC cancer line [19,20].

3.2. Description Phenolic Compounds with Anticancer Activities against Esophageal Cancer

3.2.1. Moscatilin

Moscatilin or “Dendrophenol” (C₁₇H₂₀O₅, Mol. wt. = 304.34 g mol⁻¹) is a chalcone-bibenzyl derivative isolated from the orchid Dendrobium loddigesii. This plant is mainly found in Laos, Vietnam, and China [49]. Despite its multiple biological properties, it has activities against ESCC lines CE81T/VGH (IC₅₀ = 7.0 µM) and EAC lines BE3 (IC₅₀ = 6.7 µM) [19]. In vivo, moscatilin at a dose of 50 mg/kg reduces tumor mass by almost 50% in mice artificially induced with the CE81T/VGH line [21]. Chen et al. [19] revealed that the activity of this substance involves induction of apoptosis (by increasing early apoptotic cells such as PI− and annexin-V+), increased caspase activity, and cell cycle arrest in G2/M phase (through increased Plk1 and cyclin B1 expression, as well as increased phosphorylation of Cdc25c) in ESCC and EAC cells. Moscatilin is non-toxic to normal non-immortalized human oral fibroblast cells [49] and non-tumoral mammary epithelial cells [50]. Similarly, repeated use of moscatilin over 28 days does not lead to renal and hepatic complications [21]. See

Table 2. Summary of in vitro and in vivo anticancer efficacy of phenolic compounds.

Compounds	In Vitro Cancer Activities	Animal Model	Cell Lines for In Vivo Assays	In Vivo Activities	Ref.
Moscatilin	CE81T/VGH (IC50 = 7.0 µM) and BE3 (IC50 = 6.7 µM)	/	/	/	[19]
		Male nude mice	CE81T/VGH	A dose of 50 mg/kg reduces tumor mass by nearly 50% over 49 days.	[21]
Isoliquiritigenin	A concentration of 20 μM reduces proliferation of KYSE140, KYSE520, and TE-1 cells by 80%.	Femele Balb/c athymic nude mice	KYSE140	A dose of 10 mg/kg reduces tumor mass by approximately 84% within 24 days.	[22]
3-deoxysappanchalcone (3-DSC)	KYSE 30 (IC50 = 19.8 µM); KYSE 70 (IC50 = 20 µM); KYSE 410 (IC50 = 12.2 µM); KYSE 450 (IC50 = 24.7 µM); KYSE 510 (IC50 = 24.8 µM)	/	/	/	[23]
Osthole	KYSE150 (IC50 = 102.51 μM); KYSE410 (IC50 = 114.02 μM)	/	/	/	[24]
Quercetin	A concentration of 10 μM reduces proliferation of Eca-109 cells by approximately 92%.	/	/	/	[25]
Icariin	KYSE70 (IC50 = 40 μM)	Female immunodeficient mice	KYSE70	A dose of 40 μg/g reduces tumor mass by approximately 71% over 4 weeks.	[26]
	Eca109 (IC50 = 38.59 μM); TE-1 (IC50 = 42.21 μM)	Male athymic nude mice	Eca109	A dose of 120 mg/kg reduces tumor mass by approximately 32% over 4 weeks.	[27]
Purpurogallin	A concentration of 40 μM reduces proliferation by approximately 95% (KYSE30), 51%(KYSE70), 36% (KYSE410), 48% (KYSE450), and 59% (KYSE510)	Female mice	EG30 and LEG34 human ESCC	A dose of 100 mg/kg reduces tumor mass by approximately 64% in 21 days and 50% in 31 days, for tumors induced by EG30 and LEG34 cells, respectively.	[28]
	KYSE510 (IC50 ≈ 7 µM)	/	/	/	[29]
(6,7,4′-THIF) or 6,7,4′-Trihydroxyisoflavone	A concentration of 20 μmol/L, reduces proliferation by approximately 35% (KYSE 30); 42% (KYSE 450), and 82% (KYSE 510)	/	/	/	[30]
Genistein	Eca-109 (IC50 = 5 μM); EC9706 (IC50 = 15 μM); CaES-17 (IC50 = 12 μM); Het-1A (IC50 = 125 μM)	Nude mice	Eca-109	A dose of 10 mg/kg reduces tumor mass by approximately 63% over 42 days.	[31]
Hesperetin	Eca-109 (IC50 = 200 μM)	Female Balb/c nude mice	Eca-109	A dose of 90 mg/kg reduces tumor mass by approximately 74% over 30 days.	[33]
Baohuoside-I	Eca-109 (IC50 = 24.8 µg/mL)	Female Balb/c nude mice	Eca-109	A dose of 25 mg/kg reduces tumor mass by approximately 83% over 21 days.	[34]
Curcumin	TE-1 (IC50 = 19.23 μM), TE-5 (IC50 = 19.45 μM), TE-6 (IC50 = 7.03 μM), TE-8 (IC50 = 8.88 μM), TE-10 (IC50 = 12.91 μM), TE-11 (IC50 = 8.98 μM), TE-11R (IC50 = 34.98 μM), T.Tn (IC50 = 19.66 μM), and HCE-4 (IC50 = 8.94 μM)	C57BL/6 male mice	TE-11R	A dose of 5000 ppm reduces tumor mass by approximately 43% over 49 days with intraperitoneal administration.	[35]
	KYSE30 (IC50 = 5.42 µg/mL)	/	/	/	[36]
	A concentration of 60 μM reduces proliferation across all cell lines (TE-1, TE-8, KY-5, KY-10, YES-1, and YES-2), with the percentage of remaining cells ranging from 10.9% to 36.3%.	/	/	/	[37]
Proanthocyanidins	Eca-109 (IC50 = 37.158 µg/mL)	/	/	/	[38]
	IC50 between 50–100 µg/mL for OE19, JHAD1, and OE33 cells	Male NU/NU athymic mice	OE19	A dose of 250 µg/mouse reduces tumor mass by approximately 67% over 19 days.	[20]
Gallic acid	TE-2 (CPI50 = 0.3 mg/mL)	/	/	/	[39]
Sesamin	A concentration of 40 μM reduces proliferation by approximately 60% in KYSE150, EC9706, Eca-109, and TE-2 cells.	Female nude mice	Eca-109	A dose of 150 mg/kg reduces tumor mass by approximately 48% over 21 days with oral administration.	[40]
(-)-epigallocatechin-3-gallate	KYSE 510 (IC50 = 18 μM)	/	/	/	[29]
Theaflavin-3-3′-digallate	KYSE 510 (IC50 = 18 μM)	/	/	/	[29,41]
Theaflavate A	KYSE 510 (IC50 = 18 μM)	/	/	/	[29]
Lapachol	WHCO1(IC50 = 24.1 µM)	/	/	/	[42]
	KYSE30, KYSE450, KYSE510 (IC50 ≈ 2 µM)	/	/	/	[43]
β-lapachone	WHCO1 (IC50 = 1.6 mM)	/	/	/	[42]
Pristimerin	A concentration of 1.5 μmol/L reduces cell proliferation in Eca-109 by 50%.	male BALB/c nude mice	Eca-109	A dose of 1.5 μmol/L reduces tumor mass by approximately 70% over 21 days with intraperitoneal administration.	[44]
	EC9706 (IC50 = 1.98 µM), Eca109 (IC50 = 1.76 µM), KYSE30 (IC50 = 1.13 µM)	/	/	/	[45]
Plumbagin	KYSE150 (IC50 = 6.4 μM); KYSE450 (IC50 = 8.0 μM)	Female BALB/c nude mice	KYSE150	A dose of 2 mg/kg reduces tumor mass by approximately 63% over 21 days with intraperitoneal administration.	[46]
Corilagin	Eca-109 (IC50 = 28.58 μM), and KYSE150 (IC50 = 35.05 μM)	Athymic nude mice	Eca109	A dose of 20 mg/kg reduces tumor mass by approximately 75% over 21 days with oral administration.	[47]
Griffipavixanthone	A concentration of 10 μM reduces cell proliferation by 48% in TE-1 cells and 42% in KYSE150 cells.	/	/	/	[48]

CPI₅₀: cell proliferation inhibition 50%; IC₅₀: Inhibitory Concentration 50%.

for a summary of biological activities.

3.2.2. Isoliquiritigenin

Isoliquiritigenin is a chalcone-flavonoid isolated from Glycyrrhiza glabra, a plant native to southern Europe and Asia [51]. In vitro, this molecule inhibited cell growth and proliferation in ESCC KYSE140, KYSE520, and TE1 cancer cells [22]. Isoliquiritigenin exerts its anti-ESCC activity at several levels: induces cell cycle arrest at G0/G1 phase by reducing cyclin D1 expression; down-regulates AP-1 family proteins (Jun and Fos); and significantly reduces EGFR activation and its downstream signaling pathway Akt and ERK1/2 [22]. In vitro toxicology studies of Isoliquiritigenin on a broad range of human normal cells have demonstrated its safety on MCF-10A cells from the breast at concentration ≤ 100 µM [52,53] and H184B5F5/M10 at concentration ≤ 10 µM, HELF from lung [54], AML-12 Hepatocyte at concentration < 5 µM [55], T-HESCs from the uterus Endometrium at concentration ≤ 75 µM [56], GES-1 from the stomach at dose < 20 µM [57], HUVEC Endothelia [58], SG from the mouth (IC₅₀ = 386.3 ± 29.7 µM) at concentration ≤ 400 µM [59], IEC-6 from the small intestine at concentration ≤ 100 µM [60], and H22 from the brain (neuroprotective) [61].

3.2.3. 3-Deoxysappanchalcone (3-DSC)

3-deoxysappanchalcone is a chalcone found in Caesalpinia sappan L. (Leguminosae), a plant native to southern China, Malaysia, and south-central India [62]. In addition to its antiviral, anti-allergic, antioxidant, and anti-inflammatory activities [63], 3-deoxysappanchalcone also exhibits anti-ESCC activities against KYSE 410 (IC₅₀ = 12.2 µM), KYSE 30 (IC₅₀ = 19.8 µM), KYSE 70 (IC₅₀ = 20 µM), KYSE 450 (IC₅₀ = 24.7 µM), and KYSE 510 (IC₅₀ = 24.8 µM) cell lines [23]. The mechanisms by which this compound acts against ESCC cells include induction of apoptosis via the JNK/p38/MAPK signaling pathway, cell cycle arrest in the G2/M phase, and production of ROS [23]. The work of Fu et al. [64] demonstrated in vitro safety on healthy cells HaCaT, JB6CI41-5a (JB6), and Normal Human Dermal Fibroblasts (NHDF), as well as in vivo safety following acute administration in mice at concentrations ≤ 20 µM, even after 74 h of exposure.

3.2.4. Osthole

Osthole is a natural coumarin extracted from several medicinal plants, such as Angelica pubescens and Cnidium monnieri [65]. This compound exhibits a diverse range of biological activities, including antitumor, anti-inflammatory, neuroprotective, immunomodulatory, and hepatitis-suppressive effects [66]. Among its antitumor activities, osthole demonstrates activity against the ESCC phenotype of esophageal cancer with IC₅₀ of 102.51 μM and 114.02 μM for KYSE150 and KYSE410, respectively [24]. Osthole acts by inducing G2/M phase arrest and apoptosis in ESCC cells through decreased expression of cyclin B1, Bcl-2, Cdc2, PARP1, PI3K, Survivin, and phosphorylated AKT (p-AKT); as well as increased expression of PTEN, cleaved PARP1, BAX, and cleaved Caspases 3 and 9 [24]. Osthole shows no adverse effects on acute oral administration at 2000 mg/kg in mice [67]. However, its LD₅₀ in acute intraperitoneal administration is 750 mg/kg. Only doses below 25 mg/kg are without adverse effect in subchronic oral administration for 45 days [68]. Osthole is cytotoxic in vitro on normal liver cell lines (L-02) or induces cell apoptosis [69], and significantly affects the immune response negatively [70], although it has no adverse effect on the kidney [71].

3.2.5. Quercetin

An organic compound from the flavonoid family, specifically flavonols, quercetin is found in a diverse range of food plants (grapes, onions, berries, broccoli, cherries, and citrus fruits) [72]. It is mainly known for its antioxidant activities, as well as for the treatment of diseases caused by stress and oxidants [72]. It also possesses anti-ESCC activities and acts by significantly inhibiting the proliferation, migration, and invasion of Eca-109 cells at 10 μg/mL concentration [25]. Their anti-ESCC activity is based on reduced expression of MMP2, VEGF-A, and MMP9 proteins involved in angiogenesis and tumorigenesis [25,73]. Toxicologically, quercetin is non-toxic when administered subchronically (98 days) at doses of 250 mg/kg in CD2F1 mice [74]. High doses of quercetin cause mutagenic, hepatic, prooxidant, and renal complications [75]. Acutely, 3807 mg/kg is non-toxic in BALB/c mice [76]. In vitro, quercetin exhibited cytotoxicity against normal MRC-5 (human lung fibroblasts) cells with an IC₅₀ > 80 μM, in contrast to doxorubicin (IC₅₀ = 0.9 μM) commonly used against cancer in the same cell line [77].

3.2.6. Icariin

Icariin, a flavonol glycoside, is the primary bioactive constituent isolated from Epimedium (Berberidaceae), a plant native to China [78]. Among its multiple biological properties is anti-ESCC activity against KYSE70 (IC₅₀ = 40 μM) [26], Eca-109 (IC₅₀ = 38.59 μM) and TE1 (IC₅₀ = 42.21 μM) lines [27]. Icariin exerts its action by inducing G2/M-phase cell cycle arrest, apoptosis via ROS production, and Caspase 9 activity, and reducing intracellular glutathione (GSH) levels and NADPH oxidase activity, as well as cell migration and viability, through suppression of the STAT3 and PI3K/AKT pathways [26,27]. In vitro toxicology studies have reported that this molecule is non-toxic against HEK-293 human kidney cells [79]. Other authors, such as Zhu et al. [80] and Song et al. [81], have also reported the safety of Icariin on normal cell lines.

3.2.7. Purpurogallin

Purpurogallin is a natural aglycone isolated from plants of the genus Quercus spp., with the chemical formula C₁₁H₄O(OH)₄ [82]. Currently, its activities against esophageal cancer have only been reported on ESCC types, specifically KYSE30, KYSE70, KYSE410, KYSE450, and KYSE510, with IC₅₀ ≈ 7 µM [28,29]. In vivo in mice, purpurogallin at 100 mg/kg suppressed the growth of patient-derived ESCC tumors [28]. Its anti-ESCC mechanism relies on inhibition of the MEK1/2, ERK1/2 signaling pathways, as well as inhibition of cell cycle arrest at the G2/S phase via reduction of cyclin A2 and B1 expression [28]. Purpurogallin at a dose of 100 mg/kg has no adverse effects when administered consecutively over 14 days, and is harmless to the liver, kidney, and spleen after repeated administration over 31 days [28]. This effect on the liver is supported by the work of Wu et al. [83], who demonstrated its hepatoprotective effect in vitro and in vivo. It also plays a preventive role against the onset of hypercholesterolemic atherosclerosis [84]. Thanks to its strong antioxidant capacity, purpurogallin protects normal cells (HaCaT keratinocytes) from damage and apoptosis induced by UVB radiation [85].

3.2.8. (6,7,4′-THIF) or 6,7,4′-Trihydroxyisoflavone

6,7,4′-Trihydroxyisoflavone is a natural hydroxyisoflavone found in the Capsicum annuum plant of the Solanaceae family [86]. It inhibits proliferation and increases apoptosis by targeting the Pin1 protein that controls the cell cycle (G0-G1/S transition) [30]. 6,7,4′-THIF has neuroprotective effects against SH-SY5y neuroblastoma cells alone and exposed to CoCl₂ [87].

3.2.9. Genistein

Genistein is a phytoestrogen belonging to the isoflavone class (7-hydroxyisoflavone) commonly found in variety food vegetables, such as soybeans and broad beans [88]. Its structure resembles that of endogenous estrogens [89]. Its anti-ESCC activity in vitro revealed IC₅₀ of 5 μM, 12 μM, and 15 μM, respectively, against Eca-109, CaES-17, and EC9706 cell lines [31]. In vivo, genistein at a dose of 10 mg/kg significantly reduced the size of artificially induced ESCC tumors in mice over 42 days. Moreover, genistein potentiates the in vivo effect of GLPG0634 and MK-2206, two molecules with antiproliferative effects [31]. It exerts its action by promoting apoptosis, preventing cell proliferation, and arresting the cell cycle at the G0/G1 phase by inhibiting expression of EGFR signaling pathways (MDM2/AKT/p53 and STAT3-JAK1/2) [31]. Acute administration in mice of doses below 250 mg/kg genistein does not produce toxic effects but rather has a beneficial effect on biochemical and antioxidant markers [90]. Okazaki et al. [91] reported that this molecule had no adverse biochemical, hormonal, or reproductive effects in animals of either sex when administered subacutely for 28 days at a dose of 120 mg/kg. Similarly, genistein is harmless at 50 mg/kg when administered chronically, and is non-clastogenic in vivo [92,93]. Genistein has no carcinogenic activity in rats exposed for two years to 5, 100, or 500 ppm for males and 5 or 100 ppm for females. The 500 ppm dose induced carcinogenic effects in female rats with severe estrogenic disruption [94]. Genistein has good intestinal absorption properties [95].

3.2.10. Hesperetin

Hesperetin is a flavanone, a subgroup of Dihydroflavonoids, found in several citrus juices [96]. It possesses anti-inflammatory, antioxidant, antiviral, antihyperglycemic, blood lipid-modulating, antiallergic, and cholesterol-lowering anticancer properties [97]. In vitro, Hesperetin also possesses anti-ESCC activity against the Eca109 cell line with an IC₅₀ > 200 μM [32,33]. This compound acts by inducing an increase in ROS, cleaved caspase-3 and -9, Bax protein, Apaf-1, and SuFu, and decreasing levels of Survivin and intracellular Bcl-2, which are involved in apoptosis [32]. It also suppressed the expression of cyclin D1, phosphorylated PI3K/AKT, MMP-9, and MMP-2, and increased phosphorylated p21 and PTEN, with consequent inhibition of proliferation and cell cycle arrest at the G0/G1 phase [33]. In vivo, in xenograft mice, the combination of hesperetin and 5-fluorouracil has a synergistic anticancer effect on an Eca-109-induced cancer model after 21 days [33]. In vitro, hesperetin is non-cytotoxic to GES-1 gastric epithelial cells and has a better effect than cisplatin [98]. Despite demonstrating cardioprotective effects [99], testicular protection, anti-apoptotic spermatogonia stem cells [100], anti-hyperuricemia [101], anti-lipotoxicity [102], protection against heavy metal toxicity [103], real-life toxicological studies remain virtually absent.

3.2.11. Baohuoside-I

Baohuoside I, also known as Icariside II, is a prenylated flavonoid (glycosyloxyflavone) from Epimedium koreanum, a medicinal plant distributed from southern Russia to eastern China and from Korea to Japan [104,105]. It is renowned for its anticancer properties, including anti-ESCC activities with an IC₅₀ of 24.8 µg/mL on the Eca-109 cell line. Wang et al. [34] reported that 25 mg/kg of this compound significantly reduced the size of tumors induced with the Eca109 cell line in nude Balb/c mice. Its mechanism of action in vitro and in vivo is based on the induction of apoptosis through decreased expression of β-catenin, cyclin D1, and survivin [34]. Subacute toxicity studies lasting 15 days at doses ≤ 60 mg/kg revealed no signs of toxicity in mice [106]. In vitro, cytotoxicity studies revealed that Baohuoside I has an IC₅₀ of 51 µM on normal pancreas cell lines hTERT-HPNE [107].

3.2.12. Curcumin

Curcumin, or diferuloylmethane, is a polyphenolic pigment of the diarylheptanoid group isolated from Curcuma longa (Zingiberaceae), a food and medicinal plant with multiple biological properties [108,109]. Its anti-ESCC effect was reported by Alibeiki et al. [36] on KYSE30 lines (IC₅₀ = 5.42 µg/mL); Almanaa et al. [37] on KY-10, TE-1, KY-5, YES-1, TE-8, and YES-2 lines; and Mizumoto et al. [35] on TE-1 (IC₅₀ = 19.23 μM), TE-5 (IC₅₀ = 19.45 μM), TE-6 (IC₅₀ = 7.03 μM), TE-8 (IC₅₀ = 8.88 μM), TE-10 (IC₅₀ = 12.91 μM), TE-11(IC₅₀ = 8.98 μM), TE-11R (IC₅₀ = 34.98 μM), T.Tn (IC₅₀ = 19.66 μM), and HCE-4 (IC₅₀ = 8.94 μM). It reduces the size of the ESCC tumor artificially induced in mice by 72.6% at a dose of 10,000 ppm. Curcumin induces cell cycle arrest at G2/M phase [35] and G1 phase [36] and increases SABG-positive senescence, and apoptosis by increasing caspase and Poly (ADP-ribose) polymerase (PARP) cleavage activity. It also exerts its effect on cancer stem cells [37]. Acute, repeated, and mutagenic toxicology studies have revealed that curcumin is considered safe and non-toxic [110]. However, controversy remains over its bioavailability [35,111].

3.2.13. 2,6-Bis-Benzylidenocyclohexanone (BBCH)

2,6-Bis-benzylidenocyclohexanone (BBCH) is a compound that has been investigated for its anticancer properties. Available data demonstrate its effectiveness against ESCC cell lines such as KYSE30 (IC₅₀ = 1.5 µM) [36]. BBCH exerts its anticancer effect by inducing apoptosis in KYSE30 cells and causing cell cycle arrest, particularly in the G2/M or G1 phases, thereby preventing cancer cells from dividing and proliferating. Preclinical studies in animal models, such as mice, show that BBCH reduces tumor size and weight by approximately 50% in xenograft mouse models infected with the KYSE30 cell line, indicating potential for cancer treatment in vivo [36]. Data on BBCH toxicity in mammals and humans are limited. However, preclinical studies suggest that BBCH is relatively safe at therapeutic doses, though further research is needed to fully assess its safety profile.

3.2.14. Proanthocyanidin

Proanthocyanidins are polyphenolic flavonoids (oligo- or polymers of flavan-3-ols) widely present in the nuts, fruits, seeds, vegetables, flowers, and bark of many plants [112]. They enable plants to defend themselves against abiotic and biotic stress factors [113]. The anticancer activities of proanthocyanidins have been demonstrated on both EAC (JHAD1, OE33, OE19) and ESCC (Eca-109 (IC₅₀ = 37.15 μg/mL)) phenotypes [20]. In vivo, this molecule inhibits OE19 tumor proliferation via modulation of mTOR/AKT/MAPK signaling and induction of the autophagic form of LC3B [20]. G2/M cell cycle arrest, inactivation of AKT/PI3K/mTOR, and induction of pro-apoptotic proteins (BAX, BAK1, Cytochrome C, PARP, deamidated BCL-xL), modulation of MAPKs (P-P38/P-JNK) are other mechanisms used by proanthocyanidins against ESCC cells. Mechanisms involving caspase-3 activation and attenuation of NF-κB signaling pathway activation have also been reported by Guo et al. [37]. Yamakoshi et al. [114] reported that proanthocyanidins are harmless at 4000 mg/kg in acute oral administration, at 1410 mg/kg in subchronic administration (90 days), and have no mutagenic effect according to the Ames test. Clinical studies in human subjects revealed no signs of toxicity in subjects receiving doses of 2500 mg/day for 4 weeks [115].

3.2.15. Gallic Acid

Gallic acid (3,4,5-trihydroxybenzoic acid) is a natural polyphenolic compound found in vegetables, fruits, and medicinal plants [116] and is renowned for its interesting antioxidant activities. Faried et al. [39] reported that gallic acid induced apoptosis and inhibited cell proliferation in ESCC (TE-2) cells. Gallic acid is without adverse effects when administered for 13 weeks at 128 mg/kg in F344 rats [117]. A dose of 430 mg/kg administered subacutely for 21 days had no toxic effect on the reproductive organs of rats [118]. In vitro, gallic acid is non-toxic to normal CHEK-1 esophageal cells.

3.2.16. Sesamin

Sesamin is a lignan isolated from sesame oil and seeds, as well as from the bark of Fagara plants [119]. TRIM44 levels were significantly increased in ESCC cells and tissues. In vitro, sesamin inhibits cell proliferation in ESCC cells by inhibiting NF-kB, TLR4 signaling, and TRIM44 expression. In vivo, the 150 mg/kg dose reduces tumor size and TRIM44 expression levels by 50% [40]. Regarding sesamin toxicity, Hori et al. [120] reported that it is non-genotoxic in vitro and in vivo in mice. Hepatoprotective [121], neuroprotective [122], and nephroprotective [123] effects have also been observed with sesamin. Sesamin is non-toxic in vitro against normal Vero (ATCC#CCL-81) [124] and immortalized human small airway epithelial (SAEC) cells [125].

3.2.17. (-)-Epigallocatechin-3-Gallate

Formally obtained by the condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin, (-)-epigallocatechin 3-gallate is a gallate ester [126]. It is the most abundant flavanol in green tea [127]. In addition to its significant antioxidant potential, this compound possesses anti-ESCC activity with an IC₅₀ of 17 µM against the KYSE 510 cell line [29]. Although the mechanism of action of (-)-epigallocatechin-3-gallate on esophageal cancer cells is not yet fully elucidated, the MAPK signaling pathway appears to play a key role in this process. Anticancer mechanisms involving Pin1 inhibition have been reported in other cancer types [128].

3.2.18. Theaflavin-3-3′-Digallate

Theaflavin-3-3′-digallate is one of the natural polyphenolic theaflavins isolated from black tea and belonging to the catechin class [129]. In addition to its significant antioxidant potential, this compound has anti-ESCC activity with an IC₅₀ of 18 µM on the KYSE 510 cell line [29]. Although the mechanism of action of theaflavin-3-3′-digallate on esophageal cancer cells is not yet fully elucidated, the MAPK signaling pathway appears to play a key role in this process. Anticancer mechanisms involving inhibition of cell proliferation, aromatase, and tyrosine kinase activity have been reported in other cancer types [130].

3.2.19. Theaflavate A

Theaflavate A, or theaflavic acid A, is a natural polyphenolic theaflavin isolated from black tea and belonging to the catechin class [131]. Initially known for its significant antioxidant potential, this compound also possesses anti-ESCC activity with an IC₅₀ of 18 µM on the KYSE 510 cell line [29]. Although the mechanism by which Theaflavate A acts on esophageal cancer cells has yet to be fully elucidated, numerous anticancer mechanisms (e.g., induction of apoptosis, cell cycle arrest, activation of caspase 9, 8, and 3) have been demonstrated with other theaflavins in various types of cancer [132]. This compound protects normal PC12 cells against ROS-induced mitochondrial apoptosis via activation of the Nrf2/ARE signaling pathway [131].

3.2.20. Lapachol

Lapachol is a naturally occurring 1,4-naphthoquinone first isolated in 1882 by E. Paterno from the plant Tabebuia avellanedae (Bignoniaceae) [133]. Lapachol exhibits notable activity against ESCC phenotypes, including KYSE30, KYSE450, and KYSE 510 (IC₅₀ ≈ 2 µM) [43], and WHCO1 (IC₅₀ = 24.1 µM) [42]. This molecule acts by inhibiting the RSK2 protein [43]. Lapachol is non-toxic to NIH3T3 normal fibroblast cells [42]. This compound is non-toxic upon acute oral administration, with LD₅₀ values ≥ 0.621 g/kg in mice, >2.4 g/kg in albino rats, and >0.5 g/kg/day in monkeys [134]. Guerra et al. [135] reported embryotoxicity, and Sá and Guerra [136] reported the reprotoxicity of lapachol in Wistar rats.

3.2.21. β-Lapachone

β-Lapachone is a natural ortho-naphthoquinone compound, originally found in the bark of Tabebuia avellanedae L. [137]. β-Lapachone exhibits notable activity against ESCC phenotypes, including WHCO1 (IC₅₀ = 1.6 mM) [42]. This compound induces apoptosis in cancer cells by activating the c-Jun signaling pathway and is harmless to normal NIH3T3 [42] and HDF fibroblast cells [138]. Toxicity tests reveal that the 80 mg/kg dose of β-Lapachone is harmless upon acute administration in mice [139]. Although harmless to the kidney and liver, doses ≥ 40 mg/kg in repeated administration are abortive, teratogenic, hematotoxic, and splenotoxic in rats [140].

3.2.22. Pristimerin

Prestimerin is a natural quinonemethide triterpenoid found in Celastraceae and Hippocrateaceae species [141]. It exhibits a diverse range of biological activity, including anti-ESCC activities on EC9706 (IC₅₀ = 1.98 µM), EC109 (IC₅₀ = 1.76 µM), KYSE30 (IC₅₀ = 1.13 µM) lines [44,45]. In vivo, pristimerin at a dose of 1.5 mg/kg/day reduced tumor size and weight by 71% in nude mice artificially infected with the Eca-109 cancer line after 2 weeks of treatment [44,45]. The anti-ESCC effect of this compound is based on its ability to inhibit the NF-κB pathway (inhibits TNFα activity) and induce G0/G1 phase arrest (through decreased protein expression of CDK4, CDK2, BCL-2, and cyclin E and increased CDKN1B expression and LC3-II/LC3-I ratio) [44,45]. Despite its promising activities against ESCC, the toxicity of pristimerin remains unknown, although it has no mutagenic activity [142].

3.2.23. Plumbagin

Plumbagin, or 5-hydroxy-2-methyl-1,4-naphthoquinone (C₁₁H₈O₃), is a natural naphthoquinone isolated from Plumbago zeylanica L. roots, a medicinal plant native to Florida and belonging to the Plumbaginaceae family [143]. It is renowned for its antioxidant, anti-inflammatory, antibacterial, antifungal, and anticancer properties [144]. Recently, Cao et al. [46] reported its efficacy against the ESCC phenotype with IC₅₀ of 6.4 and 8.0 μM on KYSE150 and KYSE450 cell lines, respectively. In vivo, in mice, plumbagin inhibits cell proliferation, reducing tumor size and mass by over 80% after 3 weeks of treatment at a dose of 2 mg/kg administered 5 times a week [46]. It acts by inducing cell cycle arrest and apoptosis through inhibition of STAT3-PLK1-AKT expression. Plumbagin is non-toxic at 150 mg/kg acute and 25 mg/kg subacute for 28 days in rats. Its bioavailability is 9.63 and its half-life is 5.0 h in rats [145]. This molecule is mutagenic in normal cells undergoing exponential growth [146].

3.2.24. Corilagin

Corilagin is an ellagitanin (gallotannin) isolated from Dividivi and Caesalpinia coriaria in 1951 and is now found in numerous plants, such as Phmllanthi Fructus [147]. This molecule has preventive and curative properties against several types of cancer [148]. Wu et al. [47] reported that corilagin is also effective against ESCC cancer cell lines, including Eca-109 (IC₅₀ = 28.58 μM) and KYSE150 (IC₅₀ = 35.05 μM). The 20 mg/kg dose significantly reduces tumor size in nude mice. It acts by arresting the cell cycle in the G0/G1 phase, resulting in apoptosis [47]. Toxicological studies available to date reveal that corilagin is non-mutagenic according to the Ames test [149] and non-cytotoxic in vitro to normal Vero [150], RAW264.7, BV-2 [151], MHCC97-H, SKOv3ip, and ovarian (OSE01, OSE02, and OSE03) and hepatic (Chang-liver) surface epithelial cells [152]. Corilagin is non-toxic at doses ≥ 3500 mg/kg in acute oral administration and at 1000 mg/kg for four weeks in subacute administration in mice [153].

3.2.25. Griffipavixanthone

Griffipavixanthone is a natural bixanthone found in Garcinia spp. [154,155,156]. At a concentration of 10 µM, this molecule completely inhibits the proliferation of TE1 and KYSE150 cells [48]. In vivo, the 20 mg/kg dose of griffipavixanthone prevented and reduced tumor sizes and lung metastases in mice infected with the KYSE150 cancer cell line, outperforming 5-Fluorouracil at the same dose. Griffipavixanthone acts by inhibiting AKT, decreasing cyclin B1 protein expression levels, the RAS-RAF-MEK-ERK cascade, and inducing G2/M cell cycle arrest [48]. Despite its promising activities against ESCC cells, toxicological studies on griffipavixanthone remain limited and are a future research priority.

A summary of the mechanisms of action of the various phenolic compounds is shown in Figure 2.

4. Discussion

This study, which aimed to identify phenolic compounds with effects on esophageal cancer, assess their toxicological profile, and explore future perspectives, identified 25 compounds belonging to the group of phenolic compounds with anti-ESCC properties. This large number is justified by the fact that this group of compounds is the most abundant in plants, unlike the alkaloid and terpene groups [3]. Except for osthole and hesperetin, which have moderately significant cytotoxic activities (IC₅₀ > 100 μM), all other compounds exhibit significant cytotoxic activity (IC₅₀ < 100 μM) against all ESCC lines to which they were exposed [158]. However, it is important to note that compounds such as moscatilin, genistein, lapachol, curcumin, β-lapachone, pristimerin, and plumbagin have very significant cytotoxic activities (IC₅₀ < 10 μM) against ESCC cells, approaching the activities of doxorubicin (0.9 μM). These compounds demonstrate efficacy at very low concentrations, often indicative of potent anticancer activity. This suggests they possess a significant capacity to inhibit the growth of ESCC and EAC cells at relatively low doses, offering promising prospects for future development as potential therapeutic agents against cancer. These compounds need to be thoroughly investigated, as they could revolutionize esophageal cancer therapy.

Similarly, individual studies conducted in vivo with these various compounds revealed that they reduced tumor sizes in mice more effectively than conventional anticancer drugs, a phenomenon that contrasts with the results observed in vitro. This can be explained by the fact that these compounds are potentiated by in vivo metabolism, resulting in more pronounced activity. According to Herman and Santos [159], secondary metabolites can exhibit enhanced activity during their passage through a living organism, leading to more pronounced effects. A substance may be metabolized into a toxic, inactive, less active, or active form as it passes through a living organism [160].

Phenolic compounds exhibit various mechanisms of action against esophageal cancer, providing promising alternatives to conventional treatments. These compounds induce apoptosis by increasing caspase activity and causing cell cycle arrest at different phases, such as isoliquiritigenin, hesperetin, moscatilin, and icariin, while also acting through ROS production and modulation of signaling pathways such as STAT3 and PI3K/AKT. Unlike chemotherapy (e.g., cisplatin) and radiotherapy, which cause severe side effects and can lead to resistance, phenolic compounds might offer less toxic approaches while targeting pathways such as EGFR, MAPK, and PI3K/AKT. Additionally, their ability to inhibit cell proliferation and angiogenesis (e.g., quercetin and proanthocyanidins), as well as induce oxidative stress (with hesperetin, icariin, and 3-deoxysappanchalcone), represents a potential alternative that could reduce the side effects of traditional therapies, such as those observed with bevacizumab [161,162]. Furthermore, due to their less severe side effects, phenolic compounds might help overcome some treatment resistance mechanisms [163]. While current treatments are effective, they are often limited by significant side effects and the development of resistance, which can compromise their long-term efficacy [164]. These compounds could offer interesting therapeutic alternatives to drugs such as gefitinib, cisplatin, and bevacizumab, against which several esophageal cancer cell lines have already developed resistance. The specific modulation of signaling pathways and the induction of oxidative stress could be developed to overcome the limitations of current therapies and pave the way for new therapeutic strategies.

The available toxicological studies for most of these substances, although limited, reveal that they have selective toxicity towards cancer cells, with the exception of osthole, which induces liver and immune toxicity [69,70]; lapachol and β-lapachone, which are embryotoxic [135], reprotoxic [136], teratogenic, hematotoxic, and splenotoxic [140] in rodents. The adverse effects observed following direct exposure to normal cells or administration of these compounds in animals have strong predictive value for human toxicity [38,165]. To date, only proanthocyanidin, with significant activities on EAC and ESCC phenotypes, has demonstrated its safety in human subjects in a preclinical study [115], confirming that many of these substances could offer therapeutic hope against esophageal cancer following comprehensive toxicological studies.

5. Limitations and Futures Perspectives

The compounds studied show promising potential as anticancer treatments for esophageal cancer. They exhibit various mechanisms of action and demonstrate encouraging results in inhibiting tumor growth both in vitro and in vivo. However, several challenges remain. The primary limitation of this study is the limited toxicological data available for many compounds, highlighting the need for further investigation into their safety. Additionally, the lack of in vivo studies for several substances means that the impact of metabolism on their efficacy remains unconfirmed. Future research should prioritize in vivo studies in animals and subsequently in humans through clinical trials to verify that the beneficial effects observed in vitro are sustained or enhanced. Another critical issue is the absence of bioavailability and formulation studies, which are necessary to identify the optimal administration route for these compounds. For instance, although curcumin has low oral bioavailability, it remains effective in vivo, suggesting that optimizing its dosage could improve its efficacy. Furthermore, the lack of positive controls, such as established anticancer agents, in both in vitro and in vivo experiments complicates the evaluation of the phenolic compounds’ effectiveness, as there is no direct comparison to standard treatments. Despite this, some phenolic compounds (hesperetin, moscatilin, isoliquiritigenin, and 3-deoxysappanchalcione) exhibit unique mechanisms, such as specific modulation of signaling pathways and induction of oxidative stress, which may offer novel therapeutic strategies not fully explored by traditional EC treatments. Overall, gaps in information regarding bioavailability, pharmacokinetics, toxicology, and clinical trials present significant barriers to the swift and successful clinical application of these compounds. Addressing these limitations is crucial for advancing their development into effective therapeutic options.

6. Conclusions

At the conclusion of this work, which aimed to present the phenolic compounds that could constitute alternative treatments for esophageal cancer and future research prospects for their development, it was found that proanthocyanidin and curcumin represent immediate therapeutic avenues due to their significant in vitro and in vivo activity, and their safety in human clinical trials. However, moscatilin, genistein, and pristimerin exhibit anticancer activities (≤10 µM) very close to those of doxorubicin, 5-FU, etc., although their safety has not yet been fully established. In vivo studies with these various compounds have demonstrated highly significant activity compared with the results obtained in vitro and sometimes exceed the effectiveness of conventional molecules used in esophageal cancer. Generally speaking, except for plumbagin, lapachol, and β-lapachone, all other molecules are relatively non-toxic to normal human cells and represent a promising therapeutic avenue for exploration by pharmaceutical companies in the fight against esophageal cancer. Future research should focus on aspects such as bioavailability, pharmacokinetics, toxicity, and clinical trials to facilitate a successful transition to clinical applications.