Caffeic acid and its derivatives as potential modulators of oncogenic molecular pathways: New hope in the fight against cancer.

As a phenolic acid compound, caffeic acid (CA) can be isolated from different sources such as tea, wine and coffee. Caffeic acid phenethyl ester (CAPE) is naturally occurring derivative of CA isolated from propolis. This medicinal plant is well-known due to its significant therapeutic impact including its effectiveness as hepatoprotective, neuroprotective and anti-diabetic agent. Among them, anti-tumor activity of CA has attracted much attention, and this potential has been confirmed both in vitro and in vivo. CA can induce apoptosis in cancer cells via enhancing ROS levels and impairing mitochondrial function. Molecular pathways such as PI3K/Akt and AMPK with role in cancer progression, are affected by CA and its derivatives in cancer therapy. CA is advantageous in reducing aggressive behavior of tumors via suppressing metastasis by inhibiting epithelial-to-mesenchymal transition mechanism. Noteworthy, CA and CAPE can promote response of cancer cells to chemotherapy, and sensitize them to chemotherapy-mediated cell death. In order to improve capacity of CA and CAPE in cancer suppression, it has been co-administered with other anti-tumor compounds such as gallic acid and p-coumaric acid. Due to its poor bioavailability, nanocarriers have been developed for enhancing its ability in cancer suppression. These issues have been discussed in the present review with a focus on molecular pathways to pave the way for rapid translation of CA for clinical use.

Biomedical application of chitosan-based nanoscale delivery systems: Potential usefulness in siRNA delivery for cancer therapy.

Gene therapy is an emerging and promising strategy in cancer therapy where small interfering RNA (siRNA) system has been deployed for down-regulation of targeted gene and subsequent inhibition in cancer progression; some issues with siRNA, however, linger namely, its off-targeting property and degradation by enzymes. Nanoparticles can be applied for the encapsulation of siRNA thus enhancing its efficacy in gene silencing where chitosan (CS), a linear alkaline polysaccharide derived from chitin, with superb properties such as biodegradability, biocompatibility, stability and solubility, can play a vital role. Herein, the potential of CS nanoparticles has been discussed for the delivery of siRNA in cancer therapy; proliferation, metastasis and chemoresistance are suppressed by siRNA-loaded CS nanoparticles, especially the usage of pH-sensitive CS nanoparticles. CS nanoparticles can provide a platform for the co-delivery of siRNA and anti-tumor agents with their enhanced stability via chemical modifications. As pre-clinical experiments are in agreement with potential of CS-based nanoparticles for siRNA delivery, and these carriers possess biocompatibiliy and are safe, further studies can focus on evaluating their utilization in cancer patients.

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery.

Doxorubicin (DOX) is extensively applied in cancer therapy due to its efficacy in suppressing cancer progression and inducing apoptosis. After its discovery, this chemotherapeutic agent has been frequently used for cancer therapy, leading to chemoresistance. Due to dose-dependent toxicity, high concentrations of DOX cannot be administered to cancer patients. Therefore, experiments have been directed towards revealing underlying mechanisms responsible for DOX resistance and ameliorating its adverse effects. Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling is activated to increase levels of reactive oxygen species (ROS) in cells to protect them against oxidative stress. It has been reported that Nrf2 activation is associated with drug resistance. In cells exposed to DOX, stimulation of Nrf2 signaling protects cells against cell death. Various upstream mediators regulate Nrf2 in DOX resistance. Strategies, both pharmacological and genetic interventions, have been applied for reversing DOX resistance. However, Nrf2 induction is of importance for alleviating side effects of DOX. Pharmacological agents with naturally occurring compounds as the most common have been used for inducing Nrf2 signaling in DOX amelioration. Furthermore, signaling networks in which Nrf2 is a key player for protection against DOX adverse effects have been revealed and are discussed in the current review.