**1. Introduction**

Lung cancers are the second most occurring cancers and the primary cause of cancerrelated death among both men and women worldwide [1]. In 2018, out of 9.6 million cancer-related deaths, 1.76 million were caused by lung cancers [2]. Non-Small Cell Lung Cancer (NSCLC) accounts for 85% of all lung cancers [3], and adenocarcinoma is the principal subtype makeup for 75–85% of lung cancer and related deaths [4].

Rapid metastasis of lung adenocarcinomata [5] are primarily responsible for their late diagnosis, significantly affecting patient survival [6]. Common causes of lung cancers include smoking, air pollution, occupational exposure, and genetics [6]. However, diet also plays a crucial chemoprophylactic role in lung cancers [7–9]. It is more evident from the increasing number of novel anticancer compounds discovered in common foods and drinks [10]. Besides rapid metastasis, the aggressive chemotherapeutic regimen often associated with late-stage lung cancer treatment also contributes to poor patient survival [11]. Natural products used as adjuvant therapy have promoted patient survival and quality of life [12,13]. These have created a demand for natural chemopreventive, chemoprotective, and adjuvant compounds in cancer treatment [3,12–14].

Natural products are an abundant source of novel therapeutics [14]. More than 67% of novel anticancer and antitumor drugs are natural compounds or their analog [14,15], and

**Citation:** Imam, K.M.S.U.; Tian, Y.; Xin, F.; Xie, Y.; Wen, B. Lactucin, a Bitter Sesquiterpene from *Cichorium intybus*, Inhibits Cancer Cell Proliferation by Downregulating the MAPK and Central Carbon Metabolism Pathway. *Molecules* **2022**, *27*, 7358. https://doi.org/10.3390/ molecules27217358

Academic Editors: Barbara De Filippis, Alessandra Ammazzalorso and Marialuigia Fantacuzzi

Received: 27 September 2022 Accepted: 25 October 2022 Published: 29 October 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

more than 200 compounds and derivatives are at different stages of drug development and trials [15]. Chicory (*Cichorium intybus* L.) is a widely distributed plant used as medicine, food, drink, and fodder [16]. It has been the subject of many pharmacological studies [16]. Recently, we reviewed the cytotoxic of Chicory [16], where 31 out of 87 *C. intybus* metabolites possess anticancer, antitumor, and related bioactivities. Lactucin is a phytometabolite from Chicory, phytochemically categorized as bitter Sesquiterpene Lactones (SLs). SLs have been a subject of interest in cancer research for decades, and many have reached clinical trials [15]. As indicated in Ghantous, Gali-Muhtasib, Vuorela, Saliba, and Darwiche [15] reviews, SLs bioactivity is strictly linked to three conserved structural features, e.g., (i) alkylating center reactivity, (ii) side chain and lipophilicity, and (iii) molecular geometry and electronic features. Since many of the structural features that lactucin shares with other SLs have shown antitumor bioactivity against NSCLC [15], Lactucin will likely possess these properties.

Some plants of the Asteraceae family commonly synthesize Lactucin. It is one of the ingredients of lactucarium, a milky white liquid secreted by several lettuce species, e.g., *Lactuca serriola*, *L. saligna*, *L. viminea*, *L. glareosa*, *L. sativa*, [17–19], etc. In 1970 Chicory root water extract was reported as a light-sensitive, highly potent antimalarial compound. Later Bischoff et al. [20] attributed it to Lactucin, making Chicory the most famous source of Lactucin. Besides antimalarial properties, Lactucin also exerts or potentially exerts anti-inflammatory [21], sedatives [17], anti-adipogenic [22], and anthelmintics [23] effects. Zhang et al. [24] reported Lactucin induces apoptosis and sub-G1 cell cycle arrest in HL-60 (human leukemia cancer) cells. Ren et al. [25] reported similar effect on KB (human epidermoid carcinoma; IC50 = 75 μM), and Bel 7402 (human hepatocellular carcinoma; IC50 = 55 μM) cells. Apart from these reports, the anticancer effect of Lactucin, especially on lung cancer, remains largely unexplored. A structural activity study (SAR) by Ren, et al. [25] revealed the importance of an ester group (γ-butyrolactone) and one exocyclic methylene group for the antitumor activity of Lactucin-like Guanolides. Wang, et al. [22] reported that Lactucin inhibits adipogenesis by downregulating the JAK2/STAT3 signaling pathway and subsequent clonal expansion. However, the cellular target protein of Lactucin and the affected pathway in antitumor activity is still unknown. Herein, we evaluated the anticancer potency of Lactucin using A549 and H2347 lung adenocarcinoma cell lines in vitro to identify interacting proteins and underlying molecular mechanisms.

#### **2. Results**
