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Abstract
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Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a five-year survival rate under 10% . Gemcitabine has long been the cornerstone of chemotherapy for PDAC, but its therapeutic benefit is often limited by intrinsic or acquired resistance. Numerous studies have attempted to elucidate molecular mechanisms of resistance, including upregulation of anti-apoptotic proteins, activation of survival pathways, and altered drug transport .
Gene expression patterns associated with gemcitabine sensitivity in resected pancreatic cancer tissues, highlighting differential levels of key metabolic and apoptotic genes. More recently, integrative genomic analyses in patient-derived xenograft models have revealed gene signatures predictive of gemcitabine resistance . Furthermore, noncoding RNAs, such as lnc RNA MACC1-AS1, have been implicated in gemcitabine resistance by modulating ferroptosis and gene stability. In another recent work, the upregulation of CITED4 was shown to confer gemcitabine resistance via suppression of apoptosis through BIRC2 upregulation [8]. These findings illustrate the complexity of resistance networks and point to the need for combination strategies that target multiple pathways.
Natural products possess multi-target potential and lower toxicity profiles; many have been explored as chemo sensitizers. Earlier, we studied combinations of plants like saffron and orchid extracts with anticancer activity. Eryngium caucasicum, a species in the Apiaceae family, has been shown in vitro to inhibit proliferation of melanoma B16F10 cells and to induce apoptosis selectively, using MTT and annexin V/PI assays. Some conflicting data exist: a methanolic extract of E. caucasicum did not show significant cytotoxicity in colon or liver cancer cell lines in one study. However, given its botanical potential and underexplored status in pancreatic cancer, it is a promising candidate for combination studies. Thus, although gemcitabine remains standard, resi
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