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               Pomiferin,  a  natural  prenylated  flavonoid,  modulates  drug  resistance
               mechanisms and resensitizes multidrug-resistant cancer cells
                                                   1,2
                              1
                                                                                     ,3
               Ching-Hui Su,  Chin-Chuan Hung,  Y u -Hsuan Lan,  Ching-I Hsu*
                                                                     1
               1  Department of Pharmacy, College of Pharmacy, China Medical University, Taichung
                 406040, Taiwan
               2  Department of Pharmacy, China Medical University Hospital, Taichung 404327, Taiwan
               3  Department of Pharmacy, China Medical University Beigang Hospital, Yunlin 651012,
                 Taiwan
               * E-mail: 062897@tool.caaumed.org.tw
               Abstract
                  Multidrug resistance (MDR) represents a significant obstacle in effective cancer treatment,
               often leading to chemotherapy failure and disease progression. In the present study, we explored
               the ability of pomiferin, a naturally derived prenylated flavonoid, to enhance the treatment
               sensitivity  of drug-resistant cancer cells. Human cancer cell lines,  KB  (drug-sensitive) and
               KBvin (drug-resistant), were used to investigate the potential mechanisms by which pomiferin
               overcomes  drug  resistance,  through  assessments  of  cytotoxicity,  cell  cycle  distribution,
               apoptosis,  cell  proliferation,  and  P-glycoprotein  (P-gp)–related  function  using  calcein-AM
               uptake, ATPase activity, and MDR1 shift assays. The results revealed that pomiferin exhibited
               notable cytotoxicity in both cell types, with enhanced sensitivity towards the MDR KBvin cells.
               Flow cytometric analysis demonstrated that pomiferin alone induced G1/G0 phase arrest, while
               its combination with paclitaxel significantly increased the sub-G1 population in the KBvin cells,
               suggesting  enhanced  apoptotic  activity,  as  further  confirmed  by  apoptosis  assay  results.
               Pomiferin  also  significantly  inhibited  MDR  cancer  cell  proliferation.  Further  P-gp–related
               assays  suggested  that  pomiferin  partially  interferes  with  P-gp–mediated  efflux,  though  its
               activity does not appear to involve direct modulation of ATPase function. Overall, our findings
               demonstrate  that  pomiferin  enhances  the  response  of  drug-resistant  cancer  cells  through
               multiple  mechanisms,  including  cell  cycle  modulation,  apoptosis  induction,  and  partial
               engagement with drug resistance pathways. These results support the potential of pomiferin as
               an adjuvant compound to improve the efficacy of chemotherapeutic agents in MDR cancer
               treatment.
               Keywords: Pomiferin; Cancer treatment; MDR cancer
     	
