Expression of Claudin-9 (CLDN9) in Breast Cancer, the Clinical Significance in Connection with Its Subcoat Anchorage Proteins ZO-1 and ZO-3 and Impact on Drug Resistance.

(1) Introduction: Claudin-9 (CLDN9) is a member of the claudin protein family, a critical transmembrane protein family for tight junctions that are implemented in the progression of numerous cancer types. The present study investigated the role that CLDN9, along with the subcoat proteins, Zonula Occludens (ZOs), plays in clinical breast cancer and subsequent impact on drug response of patients. (2) Methods: CLDN9 protein and CLDN9 transcript were determined and correlated with clinical and pathological indicators, together with the status of hormonal receptors. The levels of CLDN9 transcript were also assessed against the therapeutic responses of the patients to chemotherapies by using a dataset from the TCGA database. Breast cancer cell models, representing different molecular subtypes of breast cancer, with differential expression of CLDN9 were created and used to assess the biological impact and response to chemotherapeutic drugs. (3) Results: Breast cancer tissues expressed significantly higher levels of the CLDN9, with the high levels being associated with shorter survival. CLDN9 was significantly correlated with its anchorage proteins ZO-1 and ZO-3. Integrated expression of CLDN9, ZO-1 and ZO-3 formed a signature that was significantly linked to overall survival (OS) (p = 0.013) and relapse-free survival (RFS) (p = 0.024) in an independent matter. CLDN9 transcript was significantly higher in patients who were resistant to chemotherapies (p < 0.000001). CLDN9 connection to chemoresistance was particularly prominent in patients of ER-positive (ER(+)), Her-2-negative((Her-2(-)), ER(+)/Her-2(-) and triple-negative breast cancers (TNBCs), but not in patients with HER-2-positive tumors. In Her-2-negative MCF7 and MDA-MB-231 cancer cells, loss of CLDN9 significantly increased sensitivity to several chemotherapeutic drugs including paclitaxel, gemcitabine and methotrexate, which was not seen in Her-2(+) SKBR3 cells. However, suppressing Her-2 using neratinib, a permanent Her-2 inhibitor, sensitized cellular response to these chemodrugs in cells with CLDN9 knockdown. (4) Conclusions: CLDN9 is an important prognostic indicator for patients with breast cancer and also a pivotal factor in assessing patient responses to chemotherapies. Her-2 is a negating factor for the treatment response prediction value by CLDN9 and negating Her-2 and CLDN9 may enhance breast cancer cellular response to chemotherapeutic drugs.

Bioactive Molecules: Structures, Functions, and Potential Uses for Cancer Prevention and Targeted Therapies.

Cancer continues to be an increasingly pervasive and destructive disease worldwide [...].

Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents.

BACKGROUND: Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE: To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS: This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS: Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION: For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.