The　occurrence　of　multidrug　resistance　(MDR)　is　highly　associated　with　the　overexpression　of　ATP-binding　cassette　(ABC)　transporters,　among　which,　P-glycoprotein　(P-gp)　plays　one　of　the　most　important　roles.　Iso-pencillixanthone　A　(iso-PXA)　is　a　compound　isolated　from　the　marine-derived　fungus　Penicillium　oxalicum.　No　studies　on　the　anti-tumor　effect　of　this　compound　have　been　reported,　except　for　a　few　focusing　on　its　bactericidal　properties.　In　this　study,　we　found　iso-PXA　could　stimulate　P-gp　ATPase　activity　and　attenuate　P-gp　expression　to　increase　the　intracellular　drug　concentration　in　the　cervical　vincristine　(VCR)-resistant　cell　line　HeLa/VCR.　Then,　it　increased　ROS　generation,　depolarized　MMP,　promoted　the　release　of　cytochrome　c　from　mitochondria,　and　further　activated　caspase-9,　caspase-3　and　PARP　to　induce　cell　apoptosis　effectively　through　the　intrinsic　pathway.　Caspase-8　medicated　cleavage　of　Bid　into　the　truncated　form　tBid　partially　initiated　the　mitochondrial　apoptotic　events.　The　elevation　of　the　Bax/Bcl-2　ratio,　the　accumulation　of　FBW7　and　the　degradation　of　Mcl-1　accelerated　the　iso-PXA　induced　apoptotic　process.　The　HeLa/VCR　cell　xenograft　model　again　confirmed　that　iso-PXA　had　much　better　efficacy　than　vincristine　in　vivo.　Taken　together,　these　findings　demonstrated　that　iso-PXA　elicited　remarkable　anti-tumor　and　anti-MDR　activity　through　inhibiting　P-gp　expression　and　function　and　re-activating　the　intrinsic　apoptosis　pathway　in　vitro　and　in　vivo,　suggesting　it　as　a　potential　chemotherapeutic　lead　compound　in　the　treatment　of　cervical　MDR　cancers.　©　The　Royal　Society　of　Chemistry.