The presence of key hypoxia regulators, namely, hypoxia-inducible factor (HIF)-1α or HIF-2α, in tumors is associated with poor patient prognosis. Hypoxia massively activates several genes, including the one encoding the BCRP transporter that proffers multidrug resistance to cancer cells through the xenobiotic efflux and is a determinant of the side population (SP) associated with cancer stem-like phenotypes. As natural medicine comes to the fore, it is instinctive to look for natural agents possessing powerful features against cancer resistance. Hypericin, a pleiotropic agent found in Hypericum plants, is a good example as it is a BCRP substrate and potential inhibitor, and an SP and HIF modulator. Here, we showed that hypericin efficiently accumulated in hypoxic cancer cells, degraded HIF-1/2α, and decreased BCRP efflux together with hypoxia, thus diminishing the SP population. On the contrary, this seemingly favorable result was accompanied by the stimulated migration of this minor population that preserved the SP phenotype. Because hypoxia unexpectedly decreased the BCRP level and SP fraction, we compared the SP and non-SP proteomes and their changes under hypoxia in the A549 cell line. We identified differences among protein groups connected to the epithelial-mesenchymal transition, although major changes were related to hypoxia, as the upregulation of many proteins, including serpin E1, PLOD2 and LOXL2, that ultimately contribute to the initiation of the metastatic cascade was detected. Altogether, this study helps in clarifying the innate and hypoxia-triggered resistance of cancer cells and highlights the ambivalent role of natural agents in the biology of these cells.

• Keywords
• Breast cancer resistance protein, ECM reorganization, Hypericin, Hypoxia, Proteomics, Side population,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   metabolism   MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit metabolism   MeSH
• Cell Hypoxia MeSH
• Hypoxia MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Neoplasms * metabolism   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Basic Helix-Loop-Helix Transcription Factors genetics   metabolism   MeSH
• Side-Population Cells * pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• Hypoxia-Inducible Factor 1, alpha Subunit MeSH
• hypericin MeSH Browser
• Neoplasm Proteins MeSH
• Basic Helix-Loop-Helix Transcription Factors MeSH

Searching for new strategies for effective elimination of human prostate cancer cells, we investigated the cooperative cytotoxic action of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and two platinum-based complexes, cisplatin or LA-12, and related molecular mechanisms. We demonstrated a notable ability of cisplatin or LA-12 to enhance the sensitivity of several human prostate cancer cell lines to TRAIL-induced cell death via an engagement of mitochondrial apoptotic pathway. This was accompanied by augmented Bid cleavage, Bak activation, loss of mitochondrial membrane potential, activation of caspase-8, -10, -9, and -3, and XIAP cleavage. RNAi-mediated silencing of Bid or Bak in Bax-deficient DU 145 cells suppressed the drug combination-induced cytotoxicity, further underscoring the involvement of mitochondrial signaling. The caspase-10 was dispensable for enhancement of cisplatin/LA-12 and TRAIL combination-induced cell death and stimulation of Bid cleavage. Importantly, we newly demonstrated LA-12-mediated enhancement of TRAIL-induced cell death in cancer cells derived from human patient prostate tumor specimens. Our results provide convincing evidence that employing TRAIL combined with cisplatin/LA-12 could contribute to more effective killing of prostate cancer cells compared to the individual action of the drugs, and offer new mechanistic insights into their cooperative anticancer action.

• MeSH
• Amantadine analogs & derivatives   pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Cisplatin pharmacology   MeSH
• Caspase 10 metabolism   MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Prostatic Neoplasms metabolism   pathology   MeSH
• Organoplatinum Compounds pharmacology   MeSH
• BH3 Interacting Domain Death Agonist Protein metabolism   MeSH
• TNF-Related Apoptosis-Inducing Ligand metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amantadine MeSH
• BID protein, human MeSH Browser
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Browser
• Cisplatin MeSH
• Caspase 10 MeSH
• Organoplatinum Compounds MeSH
• BH3 Interacting Domain Death Agonist Protein MeSH
• TNF-Related Apoptosis-Inducing Ligand MeSH