ABSTRACT
While the early Christian Church demonstrates a deep desire to relieve physical suffering, the Greco-Roman world in which it developed lacked the same impetus to respond to human need, especially in the context of epidemic or communicable disease. Christianity's dedication to health care, and its belief that assisting the sick constituted an absolute obligation, distinguished early Christianity from its contemporary cultural milieu which regularly ignored and excluded the sick. The novelty of the Christian approach to healing can be traced to the early church's unique recognition of human need. This vision of human need, which ultimately replaced the secular Greco-Roman emphasis on reciprocal philanthropy and providing assistance only to the worthy, is clearly exemplified in the life of Christ, in responses to plague and in the writings of John Chrysostom and the Cappadocian Fathers Basil the Great, Gregory of Nyssa, and Gregory of Nazianzus. An analysis of these sources demonstrates that the early Christian Church viewed the sick not only as persons to be assisted insofar as they shared a common human nature but also individuals necessary for the salvation of the broader community as a whole. The early church's emphasis on reciprocal interdependence between healthy and sick eliminated the boundaries traditionally established between these two groups and transformed long-standing notions of contagious disease. Ultimately, the development of these attitudes toward the sick originates in a deeper truth which underlies the Christian healthcare tradition both in the ancient world and in the modern era: humanity's profound and mutual need of God, before whom all are spiritually ill.
ABSTRACT
BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors. METHODS: Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient-derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line. RESULTS: Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ-H2AX. Inhibition of autophagy also increased ROS and γ-H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy. CONCLUSIONS: PARP inhibitor-induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild-type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.
