Jorunnamycin A Suppresses Stem-Like Phenotypes and Sensitizes Cisplatin-Induced Apoptosis in Cancer Stem-Like Cell-Enriched Spheroids of Human Lung Cancer Cells

Abstract

It has been recognized that cancer stem-like cells (CSCs) in tumor tissue crucially contribute to therapeutic failure, resulting in a high mortality rate in lung cancer patients. Due to their stem-like features of self-renewal and tumor formation, CSCs can lead to drug resistance and tumor recurrence. Herein, the suppressive effect of jorunnamycin A, a bistetrahydroisoquinolinequinone isolated from Thai blue sponge Xestospongia sp., on cancer spheroid initiation and self-renewal in the CSCs of human lung cancer cells is revealed. The depletion of stemness transcription factors, including Nanog, Oct-4, and Sox2 in the lung CSC-enriched population treated with jorunnamycin A (0.5 μM), resulted from the activation of GSK-3β and the consequent downregulation of β-catenin. Interestingly, pretreatment with jorunnamycin A at 0.5 μM for 24 h considerably sensitized lung CSCs to cisplatin-induced apoptosis, as evidenced by upregulated p53 and decreased Bcl-2 in jorunnamycin A-pretreated CSC-enriched spheroids. Moreover, the combination treatment of jorunnamycin A (0.5 μM) and cisplatin (25 μM) also diminished CD133-overexpresssing cells presented in CSC-enriched spheroids. Thus, evidence on the regulatory functions of jorunnamycin A may facilitate the development of this marine-derived compound as a novel chemotherapy agent that targets CSCs in lung cancer treatment.

Target Identification of 22-(4-Pyridinecarbonyl) Jorunnamycin A, a Tetrahydroisoquinoline Derivative from the Sponge Xestospongia sp., in Mediating Non-Small-Cell Lung Cancer Cell Apoptosis

“…Jorunnamycin A was isolated from the Thai blue sponge, Xestospongia sp., which was collected by SCUBA diving in the vicinity of Si-Chang Island, Chonburi Province, Thailand [21]. Solvents, which included ethyl acetate, dichloromethane, and hexane, were distilled before use.…”

“…was able to induce apoptosis via p53 modulation, inhibit cancer metastasis, and suppress cancer stemness behaviors [17][18][19]. Recently, jorunnamycin A found in a similar blue sponge displayed intriguing antimetastatic activity and attenuated cancer stem-cell-like phenotypes [20,21], suggesting that jorunnamycin A is a potential lead compound for the development of novel anticancer agents with greater potency.…”

Caffeine Induces G0/G1 Cell Cycle Arrest and Inhibits Migration through Integrin αv, β3, and FAK/Akt/c-Myc Signaling Pathway

“…Additionally, evidence has been reported that CSC is the main factor responsible for cancer aggression, maintenance, avoidance of the immune system, and metastasis [64,65]. Single cancer cell culture under detachment conditions with the nutrients and growth factors needed to form tumor spheroids, known as single 3D spheroid-formation assay, has been used to evaluate the CSC property [66,67]. Our results distinctly revealed that the enlargement of NCI-H23 tumor spheroids in a CSC-enriched population was diminished with caffeine treatment (Figure 4d,e).…”

Lyophilized Gelatin@non-Woven Scaffold to Promote Spheroids Formation and Enrich Cancer Stem Cell Incidence

“…Compared to 2D tumor cell culture, tumor spheroids are unique in recapitulating tissue architectures, mimicking the nutrition, metabolic, and proliferative gradients of in vivo tumors, and demonstrating clinically relevant chemoresistance [ 8 , 9 , 10 , 11 ]. More importantly, studies have revealed that tumor spheroids served as surrogate systems to evaluate cancer stem cell (CSC)-related characteristics in vitro [ 12 , 13 ]. Yamazaki et al cultured liver cancer and breast cancer cell lines on a polymer thin film to promote tumor spheroid formation.…”