Jorunnamycin A induces apoptosis in pancreatic ductal adenocarcinoma cells, spheroids, and patient-derived organoids by modulating KRAS-mediated survival pathways

被引:0
作者
Khine, Hnin Ei Ei [1 ]
Suriya, Utid [2 ]
Rungrotmongkol, Thanyada [3 ,4 ]
Chamni, Supakarn [5 ,6 ]
Lu, Yanxi [7 ]
Benard, Alan [7 ]
Lan, Bin [7 ,8 ]
Mukhopadhyay, Debabrata [9 ]
Chang, David [10 ]
Biankin, Andrew [11 ]
Schneider-Stock, Regine [11 ]
Gruetzmann, Robert [7 ]
Sungthong, Rungroch [1 ]
Pilarsky, Christian [7 ]
Chaotham, Chatchai [1 ]
机构
[1] Chulalongkorn Univ, Fac Pharmaceut Sci, Dept Biochem & Microbiol, Bangkok 10330, Thailand
[2] Mahidol Univ, Fac Sci, Dept Biochem, Bangkok 10400, Thailand
[3] Chulalongkorn Univ, Fac Sci, Ctr Excellence Struct & Computat Biol, Dept Biochem, Bangkok 10330, Thailand
[4] Chulalongkorn Univ, Grad Sch, Program Bioinformat & Computat Biol, Bangkok 10330, Thailand
[5] Chulalongkorn Univ, Fac Pharmaceut Sci, Dept Pharmacognosy & Pharmaceut Bot, Bangkok 10330, Thailand
[6] Chulalongkorn Univ, Nat Prod & Nanoparticles Res Unit NP2, Bangkok 10330, Thailand
[7] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Klinikum Erlangen, Dept Surg, D-91054 Erlangen, Germany
[8] Hunan Normal Univ, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Dept Intervent Radiol & Vasc Surg, Changsha 410002, Peoples R China
[9] Mayo Clin, Coll Med & Sci, Dept Biochem & Mol Biol, Jacksonville, FL 32224 USA
[10] Univ Glasgow, Wohl Canc Res Ctr, Inst Canc Sci, Glasgow G12 8QQ, Scotland
[11] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Expt Tumor Pathol, Univ Klinikum Erlangen, D-91054 Erlangen, Germany
来源
SCIENTIFIC REPORTS | 2025年 / 15卷 / 01期
基金
美国国家卫生研究院;
关键词
Jorunnamycin A; Pancreatic ductal adenocarcinoma; KRAS mutation; KRAS G12D; Chemotherapy; Chemosensitizer; Patient-derived organoids; NATURAL-PRODUCTS; CANCER; PROTEIN; CHEMORESISTANCE; RESISTANCE; DISCOVERY; INHIBITOR; EFFICACY; MODELS;
D O I
10.1038/s41598-025-95766-5
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, frequently driven by oncogenic KRAS mutations. Among these, KRAS G12D is the most prevalent, contributing to chemoresistance and limiting the efficacy of current therapeutic strategies. This study investigates the therapeutic potential of jorunnamycin A (JA), a bioactive compound derived from the marine sponge Xestospongia, in PDAC. Molecular docking analyses were performed to assess JA's binding affinity for various KRAS protein variants. The synergistic effects of JA in combination with standard chemotherapeutic agents were evaluated using the Bliss independence model in pancreatic cancer cell lines and patient-derived PDAC organoids harboring distinct KRAS mutations. Furthermore, western blot analysis was performed to examine the impact the molecular mechanisms underlying JA's anticancer activity. JA demonstrated potent anticancer activity against PDAC cells, irrespective of their KRAS mutation status. In silico molecular docking and protein suppression studies indicated a strong binding affinity between JA and KRAS G12D. Synergistic interactions between JA and various PDAC chemotherapeutic agents, including oxaliplatin, SN-38, paclitaxel, 5-fluorouracil, and gemcitabine, were observed using the Bliss independence model. Notably, co-treatment with JA at a 10-fold lower concentration significantly enhanced the cytotoxicity of oxaliplatin, reducing its IC50 values around tenfold. This synergistic impact was further validated in both KRAS G12D spheroids and patient-derived PDAC organoids harboring KRAS G12D and other KRAS variants. Mechanistically, the JA-oxaliplatin combination enhanced caspase-3/7 activation, suppressed key KRAS-mediated survival pathways (STAT3, B/C-RAF, AKT, and ERK), and led to the downregulation of anti-apoptotic proteins (MCL-1 and BCL-2). These findings highlight JA as a promising therapeutic candidate for PDAC, particularly in the context of KRAS G12D-driven tumors. Further investigations into its pharmacokinetics and clinical feasibility are warranted to explore its full potential in PDAC treatment.
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页数:19
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