Research progress of plant-derived chemical compounds for overcoming pancreatic cancer drug resistance

Table 1 Summary of multidrug resistance proteins in pancreatic cancer

	Location	Expression trend	Primary function in drug resistance	Ref.
ABC	Barrier-protected tissues (gut, blood-brain barrier, liver, kidney)	Upregulated	Pump hydrophobic drugs out of cells to reduce intracellular concentration and transport anionic compounds such as topoisomerase inhibitors	[64-70,79,80]
P-gp	Intestinal epithelium, liver, kidney, hematopoietic system	Upregulated	ATP-dependent efflux of chemotherapeutic agents, reducing their cytotoxic efficacy	[71,81-84]
LRP	Excretory and immune tissues	Upregulated	Mediates active exclusion of drugs via nuclear export and compartmentalization mechanisms	[72-74,85-87]
Topo II	Highly proliferative tissues (hematopoietic system, intestinal crypts, germ cells), with Topo IIα dominant in cycling cells and Topo IIβ in post-mitotic cells (e.g., neurons)	Downregulated	Alterations in Topo II expression levels or activity downregulation of expression: Tumor cells reduce the expression of Topo IIα (the primary target of chemotherapeutic agents), reducing the number of available drug-binding sites. Topo II gene mutations: Mutations within drug-binding domains (e.g., the ATP- or DNA-binding regions) can impair the affinity between the enzyme and its inhibitors	[75,76,88,89]
GSTs	Detoxifying organs (liver, kidney)	Upregulated	Conjugate GSH with electrophilic compounds, reducing drug-induced oxidative stress	[77,78,90-92]

ABC: ATP-binding cassette; P-gp: P-glycoprotein; LRP: Lung resistance-related protein; Topo II: Topoisomerase II; GSTs: Glutathione S-transferases; GSH: Glutathione.

Table 2 Summary of microRNAs associated with gemcitabine resistance in pancreatic cancer

Names of ncRNAs	Genomic location	Expression	Regulated chemotherapy drugs	Ref.
miR-210	11p15.5	Upregulated	GEM	[99]
miR-30a-3p	6q13	Upregulated	GEM	[100]
miR-146a-5p	5q33.3	Downregulated	GEM	[101]
miR-21	17q23.2	Upregulated	GEM	[102]
miR-221/222	Xp11.3	Upregulated	GEM	[103]
miR126	9q34.3	Downregulated	GEM	[104]
miR-497	17p13.1	Downregulated	GEM	[105]
miR-7	9q21.11	Downregulated	GEM	[106]
miR-136-5p	14q32.31	Downregulated	GEM	[107]
miR-3662	14q32.31	Downregulated	GEM	[108]
miR-499a-5p	20q11.22	Upregulated	5-FU	[109]
miR-1291-5p	12q24.31	Downregulated	DDP	[110]
miR-181a-5p	1q32.1	Upregulated	FOLFIRINOX	[111]
miR-1307	15q21.1	Downregulated	FOLFIRINOX	[112]

ncRNAs: Non-coding RNAs; GEM: Gemcitabine; 5-FU: 5-fluorouracil; DDP: Cisplatin; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin.

Table 3 Summary of long non-coding RNAs reported to regulate chemotherapy resistance in pancreatic cancer

Names of lncRNAs	Genomic location	Expression	Regulated chemotherapy drugs	Ref.
SLC7A11-AS1	4q28.3	Upregulated	GEM	[113]
HOTTIP	7p15.2	Upregulated	DDP	[114]
PVT1	8q24.21	Upregulated	GEM	[115-118]

lncRNAs: Long non-coding RNAs; HOTTIP: HOXA transcript at the distal tip; PVT1: Plasmacytoma variant translocation 1; GEM: Gemcitabine; DDP: Cisplatin.

Table 4 Summary of circular RNAs associated with gemcitabine resistance in pancreatic cancer

Names of circRNAs	Genomic location	Expression	Regulated chemotherapy drugs	Ref.
circHIPK3	11q13.1	Upregulated	GEM	[119]
circZNF91	19q13.43	Upregulated	GEM	[120,121]
circ-MTHFD1 L	6q25.1	Upregulated	GEM	[122]
circFARP1	13q32.1	Upregulated	GEM	[123]
circLMTK2	19q13.43	Upregulated	GEM	[124]

CircRNAs: Circular RNAs; GEM: Gemcitabine.

Table 5 Summary of drug-resistance models and their applications in pancreatic cancer research

Research objective	Recommended model
High-throughput compound screening	2D cell lines or organoids
Microenvironment-mediated resistance mechanisms	Co-culture systems or PDX models
Personalized therapy validation	PDO, PDX, or organoids
Combination strategies with immunotherapy	Humanized immune system mice

2D: Two-dimensional; PDX: Patient-derived xenograft; PDO: Patient-derived organoids.

Table 6 Summary of plant-derived chemical compounds investigated for their ability to overcome drug resistance in pancreatic cancer

Names of compounds	The drug resistance mechanism or target	Experimental models	Regulated chemotherapy drugs
Curcumin	NF-κB	2D cell, PDX, xenografts models	GEM, cisplatin, oxaliplatin, and 5-fluorouracil
Resveratrol	NF-κB, STAT3	Co-culture systems models	GEM
EGCG	Akt	2D cell, xenografts models	GEM
Quercetin	PI3K/AKT/mTOR	2D cell, xenografts models	GEM
Apigenin	GSK-3β/NF-κB	2D cell, xenografts models	GEM
β-elemene	P-gp	2D cell, xenografts models	Cisplatin, gefitinib, aldesleukin, oxaliplatin, doxorubicin
Paclitaxel	Hedgehog	2D cell, xenografts models	GEM
Artemisinin	/	2D cell	GEM
Berberine	Rap1/PI3K-Akt	2D cell, co-culture systems models	Lovastatin
Vinblastine	βIVb-tubulin	CDO	Vincristine
Camptothecin	Topo-I	3D, PDX, xenografts models	GEM
Allicin	/	2D cell	5-fluorouracil
Sulforaphane	NF-κB	2D cell, xenografts models	GEM
Astragalus polysaccharides	AKT/ERK/MMP-9	2D cell, xenografts models	GEM, S-1
Lentinan	/	2D cell	GEM, S-1, PTX

NF-κB: Nuclear factor kappa B; 2D: Two-dimensional; PDX: Patient-derived xenograft; GEM: Gemcitabine; STAT3: Signal transducer and activator of transcription 3; EGCG: Epigallocatechin gallate; Akt: Protein kinase B; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mechanistic target of rapamycin; GSK-3β: Glycogen synthase kinase 3 beta; P-gp: P-glycoprotein; CDO: Cell line-derived organoids; Topo-I: Topoisomerase I; ERK: Extracellular signal-regulated kinase; MMP-9: Matrix metalloproteinase-9; PTX: Paclitaxel.