CXCL1 in Anticancer Therapy of Gastrointestinal Tumors: Comparison
Please note this is a comparison between Version 1 by Irena Baranowska-Bosiacka and Version 2 by Alfred Zheng.

Gastrointestinal tumors are a diverse group of cancers that affect organs responsible for digestion. These tumors are categorized based on their specific organ location, including head and neck cancer, esophageal cancer, gastric cancer, liver cancer, cholangiocarcinoma, pancreatic cancer, colon cancer, and rectal cancer. One area of cancer research is the interaction between cancer cells and immune cells, in which chemokines play a vital role. C-X-C motif ligand 1 (CXCL1) is a chemokine consisting of 73 amino acids and has a molecular weight of 8 kDa. Its expression is regulated at both the transcription and CXCL1 mRNA stability levels.

  • chemokine
  • cytokine
  • CXCL1
  • tumor

1. Introduction

Gastrointestinal tumors are a diverse group of cancers that affect organs responsible for digestion. These tumors are categorized based on their specific organ location, including head and neck cancer, esophageal cancer, gastric cancer, liver cancer, cholangiocarcinoma, pancreatic cancer, colon cancer, and rectal cancer. In 2021, there were an estimated 5.95 million new cases of these tumors, representing 30.9% of all cancer diagnoses [1]. Additionally, there were 4.06 million deaths caused by gastrointestinal tumors, accounting for 40.9% of all cancer-related deaths [1]. These high mortality rates highlight the need for more effective treatment options, which has led to increased research into potential therapeutic targets.
One promising area of research focuses on intercellular signaling within tumor tissue, specifically the interaction between cancer cells and the immune system [2][3][4][5][6][7][2,3,4,5,6,7]. Cytokines, extracellular signaling molecules that regulate various immune cells, play a critical role in this interaction [8]. Among cytokines, chemokines have chemotactic properties and are divided into four subfamilies based on a conservative motif at the N-terminus [9]. The CXC chemokine subfamily includes 16 representatives in humans, which are divided based on their ability to activate the CXCR receptors [9]. C-X-C motif receptor 2 (CXCR2) ligands, including C-X-C motif ligand 8 (CXCL8, interleukin-8 (IL-8)), are the most frequently studied chemokines, followed by CXCL1.
CXCL1 is a chemokine consisting of 73 amino acids and has a molecular weight of 8 kDa [10]. Its expression is regulated at both the transcription and CXCL1 mRNA stability levels [11][12][11,12]. This chemokine activates the CXCR2 receptor at concentrations of several nM [13], making CXCR2 its most significant receptor. At approximately 100-fold higher concentrations, CXCL1 can also activate the CXCR1 receptor [13]. However, the role of CXCR1 in the physiological and pathological functions of CXCL1 appears to be less significant.
Another receptor for CXCL1 is ACKR1 [14], though the importance of this receptor remains unclear. ACKR1 seems to regulate the availability of various chemokines, including CXCL1 [15], and may participate in the transport and distribution of CXCL1 within the intercellular space [16].
Activation of the CXCR2 receptor by CXCL1 triggers signal transduction. Heterotrimeric G proteins, particularly the inhibitory guanine nucleotide regulatory protein (Gαi), are directly activated by CXCR2 [17]. Intracellularly, many proteins bind directly to CXCR2 [18], playing a crucial role in signal transduction, with some signaling pathways operating independently of G proteins.
Activation of CXCR2 by CXCL1 induces cell migration. Among blood cells, neutrophils exhibit the highest expression of CXCR2, making CXCL1 an essential chemoattractant for neutrophils [9][19][9,19]. Furthermore, CXCL1 displays mitogenic properties, demonstrated on melanoma cells as one of the chemokine’s first identified properties. As a result, CXCL1 was initially referred to as melanoma growth-stimulatory activity (MGSA) [20].

2. CXCL1 as a Therapeutic Target in Anticancer Therapy of Gastrointestinal Tumors

As described above, CXCL1 plays a significant role in the molecular processes of gastrointestinal tumors. In theory, it is possible to develop anticancer therapy targeting CXCL1. However, the most important receptor for CXCL1 is CXCR2 [9], which is also activated by other CXC chemokines, including CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8. Therefore, a better therapeutic approach would be to target CXCR2 instead of CXCL1, which would block the effects of not only CXCL1 but also the other CXC chemokines listed above.
The most well-known and commonly tested CXCR2 antagonist as an antitumor agent is SB225002 (N-(2-hydroxy-4-nitrophenyl)-N’-(2-bromophenyl)urea) [21][242]. This compound has demonstrated antitumor activity, reducing the viability of SCC158 and HN30 oral squamous cell carcinoma cell lines [22][243]. It has also been shown to have no toxicity to the immortalized keratinocyte lineage HaCaT. In addition, SB225002 reduced the proliferation and migration of RBE and SSP25 intrahepatic cholangiocellular carcinoma cell lines in vitro [23][158]. Moreover, SB225002 inhibited the growth of cholangiocellular carcinoma tumors in mice [23][158]. However, it should be noted that SB225002 is not only a CXCR2 inhibitor but also binds to β-tubulin [24][25][244,245], leading to destabilization of microtubules and antimitotic activity of SB225002.
Additionally being tested are other CXCR2 antagonists that also inhibit CXCR1 activity. CXCL1 only activates CXCR2 at low concentrations, while CXCL8 activates both CXCR1 and CXCR2 at low concentrations [26][246]. Therefore, the use of dual CXCR1/CXCR2 antagonists allows for the inhibition not only of CXCL1 and other CXCR2 ligands but also of CXCL8. SCH-527123 is one such compound being tested [27][28][247,248]. SCH-527123 inhibits the proliferation and migration of colorectal cancer cell lines HCT116 and Caco2 in vitro [29][249]. SCH-527123 also sensitizes these cells to anticancer drugs, as demonstrated by experiments involving oxaliplatin [29][249]. In vivo studies in mice have confirmed that SCH-527123 exhibits anticancer activity and sensitizes colorectal cancer cells to oxaliplatin [29][249].
CXCR2 antagonists are currently under investigation in clinical trials as potential therapeutic agents (Table 1). On the ClinicalTrials.gov website (https://clinicaltrials.gov/ct2/home, accessed on 5 May 2023), a search using the receptor name “CXCR2” revealed 29 distinct clinical trials involving CXCR2 antagonists. Additional search results appear when entering the names of specific drugs.
Table 1.
CXCR2 inhibitors in selected clinical trials. Source: ClinicalTrials.gov NIH U.S. National Library of Medicine website.
Typically, a particular CXCR2 antagonist is examined for its efficacy in treating a specific group of diseases. For instance, SX-682 is being studied as a potential anticancer agent, while Ladarixin is being explored as a treatment for type 1 diabetes. Danirixin (GSK1325756), on the other hand, is being tested for lung diseases such as COPD and influenza. AZD5069 is under investigation as both an anticancer drug and a treatment for lung diseases such as COPD and asthma. Meanwhile, SB656933 is being examined as a potential therapeutic option for COPD and cystic fibrosis.
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