Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part II: targeting cell cycle events, caspases, NF-κB and the proteasome.

Background: Endoplasmic reticulum stress (ERS), the unfolded protein response (UPR) and apoptosis signal transduction pathways are fundamental to normal cellular homeostasis and survival, but are exploited by cancer cells to promote the cancer phenotype.

Objective: Collateral activation of ERS and UPR role players impact on cell growth, cell cycle arrest or apoptosis, genomic stability, tumour initiation and progression, tumour aggressiveness and drug resistance. An understanding of these processes affords promising prospects for specific cancer drug targeting of the ERS, UPR and apoptotic pathways.

Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part I: targeting p53, Mdm2, GADD153/CHOP, GRP78/BiP and heat shock proteins.

Background: In eukaryotes, endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are coordinately regulated to maintain steady-state levels and activities of various cellular proteins to ensure cell survival.

Objective: This review (Part I of II) focuses on specific ERS and UPR signalling regulators, their expression in the cancer phenotype and apoptosis, and proposes how their implication in these processes can be rationalised into proteasome inhibition, apoptosis induction and the development of more efficacious targeted molecular cancer therapies.

Method: In this review, we contextualise many ERS and UPR client proteins that are deregulated or mutated in cancers and show links between ERS and the UPR, their implication in oncogenic transformation, tumour progression and escape from immune surveillance, apoptosis inhibition, angiogenesis, metastasis, acquired drug resistance and poor cancer prognosis.

Combination of tunicamycin with anticancer drugs synergistically enhances their toxicity in multidrug-resistant human ovarian cystadenocarcinoma cells.

Background: The pharmacologic modulatory effects of the antibiotic, tunicamycin (TM), on multidrug-resistant human UWOV2 ovarian cancer cells are reported. The UWOV2 cell line was derived from a cystadenocarcinoma in a patient refractory to combination chemotherapy with actinomycin D, vincristine (VCR), cis-diaminedichloroplatinum (II) (CDDP) and doxorubicin (DXR). In an attempt to explain drug resistance in this cell line, we examined the effects of TM on their sensitivity to various anticancer drugs, the uptake, efflux and retention of [3H]VCR, and their ability to bind [14C]DXR and [3H]azidopine (AZD), a photoaffinity label of the multidrug transporter, P-glycoprotein (Pgp).