Hybrid anticancer agents: isothiocyanate-progesterone conjugates as chemotherapeutic agents and insights into their cytotoxicities.

New hybrid molecules of isothiocyanate and progesterone and their metal complexes were synthesized exhibiting promising anti-proliferative and pro-apoptotic activity against breast and prostate cancer cells. These metal complex compounds exploited an existing cellular transport pathway for delivery of cytotoxic isothiocyanate moiety across cell membrane resulting in the inhibition of cell viability and inducing apoptosis. The highest apoptotic action was shown by the copper complex, which was mediated through the inhibition of Akt signaling similar to the one shown by isothiocyanate compounds.

Response to dual blockade of epidermal growth factor receptor (EGFR) and cycloxygenase-2 in nonsmall cell lung cancer may be dependent on the EGFR mutational status of the tumor.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have demonstrated clinical benefit in patients with nonsmall cell lung cancer (NSCLC), particularly those with tumors that have EGFR-TK domain mutations. Moreover, the EGFR and cyclooxygenase (COX)-2 pathways are known to enhance the procarcinogenic effects of each other in different tumor types. Therefore, it was hypothesized that tumor EGFR mutation status may influence the effectiveness of simultaneous EGFR and COX-2 inhibition in patients with NSCLC.

Copper conjugates of nimesulide Schiff bases targeting VEGF, COX and Bcl-2 in pancreatic cancer cells.

Copper conjugates of Schiff base derivatives of nimesulide (1), a well-known cyclooxygenase-2 (COX-2) inhibitor, were synthesized, structurally characterized and evaluated for their COX selectivity indices and cytotoxicities on pancreatic tumor, BxPC-3 (COX-2 positive) and MiaPaCa (COX-2 negative) cell lines. Copper conjugates exhibit distorted square planar geometries as revealed by the single crystal X-ray structure determination of Cu(L1)(2) and show significant growth inhibition in both cell lines (IC50 values 3-26 microM for COX-2 positive and 5-9 microM for COX-2 negative cell line) than the parent nimesulide (35 microM for COX-2 positive and >100 microM for COX-2 negative cell line). The mechanistic pathway for the biological activity involves inhibition of vascular endothelial growth factor (VEGF) and COX inhibition, as well as down regulation of antiapoptotic Bcl-2 and Bcl-(XL) proteins.

c-Myc-induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-kappa B activity in pancreatic cancer cells.

Purpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents.

Experimental Design: Stable overexpression or small interfering RNA (siRNA)-mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line.

A novel copper complex of 3-benzoyl-alpha methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway.

Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE(2)) in PC. Here the authors report the synthesis and biological activity of a novel COX-2 inhibitor, FPA-306, and its effects on PC cells with different levels of COX-2 expression.

Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells.

We report the synthesis of novel 1:1 Schiff base copper complexes of quinoline-2-carboxaldehyde showing dose-dependent, antiproliferative, and proapoptotic activity in PC-3 and LNCaP prostate cancer cells. We found that quinoline thiosemicarbazone 2 (FPA-137) was the most potent and inhibited proteosome activity in intact human prostate cancer PC-3 and LNCaP cells (IC50 of 4 and 3.2 microM, respectively) compared to clioquinol and pyrrolidine dithiocarbamate (IC50 of 10 and 20 microM), supporting the novelty of 2.

Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells.

Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3'-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)-positive hormone-responsive and -nonresponsive prostate cancer cells.

Down-regulation of Jagged-1 induces cell growth inhibition and S phase arrest in prostate cancer cells.

Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in many tissues. It has been reported that Jagged-1, a Notch ligand, is significantly over expressed in metastatic prostate cancer compared to localized prostate cancer or benign prostatic tissues. Therefore, deregulation of Jagged-1 protein levels may play a role in prostate cancer cell growth and progression.

Synthesis, molecular characterization, and biological activity of novel synthetic derivatives of chromen-4-one in human cancer cells.

The synthesis and characterization of Schiff base derivatives of 3-formylchromone 3-6 (FPA-120 to FPA-123), the minimal biologically active structural motif of soy isoflavone, genistein, and their copper(II) complexes 7-10 (FPA-124 to FPA-127) are reported here. These copper complexes possess distorted square-planar geometries capable of stabilizing Cu2+/Cu+ redox forms. The molecular modeling study revealed that the key interaction of the metal complexes was with amino acids in the pleckstrin homology (PH) and the kinase domain of the PKB (Akt) protein.

Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.

Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity.