Current Cancer Drug Targets - Volume 15, Issue 1, 2015

Microtubule drugs have been widely used in cancer chemotherapies. Although microtubules are subject to regulation by signal transduction mechanisms, their pharmacological modulation has so far relied on compounds that bind to the tubulin subunit. Using a cell-based assay designed to probe the microtubule polymerization status, we identified two pharmacophores, CM09 and CM10, as cell-permeable microtubule stabilizing agents. These synthetic compounds do not affect the assembly state of purified microtubules in vitro but they profoundly suppress microtubule dynamics in vivo. Moreover, they exert cytotoxic effects on several cancer cell lines including multidrug resistant cell lines. Therefore, these classes of compounds represent novel attractive leads for cancer chemotherapy.

Targeting angiogenesis, one of the hallmarks of carcinogenesis, using non-toxic phytochemicals has emerged as a translational opportunity for angioprevention and to control advanced stages of malignancy. Herein, we investigated the inhibitory effects and associated mechanism/s of action of Procyanidin B2-3,3"-di- O-gallate (B2G2), a major component of grape seed extract, on human umbilical vein endothelial cells (HUVECs) and human prostate microvascular endothelial cells (HPMECs). Our results showed that B2G2 (10-40 μM) inhibits growth and induces death in both HUVECs and HPMECs. Additional studies revealed that B2G2 causes a G1 arrest in cell cycle progression of HUVECs by down-regulating cyclins (D1 and A), CDKs (Cdk2 and Cdc2) and Cdc25c phosphatase and up-regulating CDK inhibitors (p21 and p27) expression. B2G2 also induced strong apoptotic death in HUVECs through increasing p53, Bax and Smac/Diablo expression while decreasing Bcl-2 and survivin levels. Additionally, B2G2 inhibited the growth factors-induced capillary tube formation in HUVECs and HPMECs. Interestingly, conditioned media (CCM) from prostate cancer (PCA) cells (LNCaP and PC3) grown under normoxic (∼21% O2) and hypoxic (1% O2) conditions significantly enhanced the tube formation in HUVECs, which was compromised in presence of conditioned media from B2G2-treated PCA cells. B2G2 also inhibited the motility and invasiveness of both HUVECs and HPMECs. Mechanistic studies showed that B2G2 targets VEGFR2/PI3K/Akt and integrin signaling molecules which are important for endothelial cells survival, proliferation, tube formation and motility. Overall, we report that B2G2 inhibits several attributes of angiogenesis in cell culture; therefore, it warrants further investigation for efficacy for angioprevention and cancer control.

Objectives: The incidence of colorectal cancer (CRC) is increasing in younger populations; the characteristics and prognosis of those younger patients are not fully understood. The aim of this retrospective study was to analyze the clinicopathological features of Chinese CRC patients under 30 years of age. Methods: We reviewed the clinical and pathological features of 83 CRC patients (33 males and 50 females) aged 13-30 years (mean, 26.1 years) selected from consecutive 5,830 patients with primary CRC referred to Shanghai Changzheng Hospital between January 1995 and December 2013. Results: The duration from the onset of symptoms to diagnosis ranged from 3 days to 24.0 months (average 4.6 months). The most common symptom at the time of diagnosis was bloody stool, occurring in 66.3% of the patients. 60.2% patients had tumors located in the rectum and 72.8% of them presented advanced diseases (TNM stage III or IV). More male patients presented as M1 stage than the female patients. Patients with CRC metastasis complained of more fatigue at the time of diagnosis than their counterparts without metastasis (31.0% vs. 5.8%, p = 0.002), but had less pronounced bowel habit change (38.0% vs. 65.4%, p = 0.017). Additionally, there were differences in histologic distributions of the tumors between patients with and without metastasis (p = 0.021). Conclusions: Compared with older CRC patients, younger CRC patients (<30 yr) have a higher frequency of mucinous adenocarcinomas, more aggressive diseases and poorer prognosis. Identification of clinicopathological characteristics in younger CRC patients would help diagnose and treat the disease in this unique group of CRC patients in the clinic.

An increasing resistance of mammalian tumor cells to chemotherapy along with the severe side effects of commonly used cytostatics has raised the urgency in the search for new anti-cancer agents. Several drugs originally approved for indications other than cancer treatment have recently been found to have a cytostatic effect on cancer cells. These drugs could be expediently repurposed as anti-cancer agents, since they have already been tested for toxicity in humans and animals. The groups of newly recognized potential cytostatics discussed in this review include benzimidazole anthelmintics (albendazole, mebendazole, flubendazole), anti-hypertensive drugs (doxazosin, propranolol), psychopharmaceuticals (chlorpromazine, clomipramine) and antidiabetic drugs (metformin, pioglitazone). All these drugs have a definite potential to be used especially in combinations with other cytostatics; the chemotherapy targeting of multiple sites now represents a promising approach in cancer treatment. The present review summarizes recent information about the anti-cancer effects of selected drugs commonly used for other medical indications. Our aim is not to collect all the reported results, but to present an overview of various possibilities. Advantages, disadvantages and further perspectives regarding individual drugs are discussed and evaluated.

Deregulated c-MYC expression is found in many human malignancies. MYC activation induces multiple lineages of hematological malignancies in single Myc transgenic mice. MYC inactivation causes tumor regression. MYC is therefore an attractive target for cancer treatment. However, little progress has been made in the development and application of targeted MYC inactivation in clinical practice. In double Myc transgenic mouse models, Myc-driven leukemogenesis and lymphomagenesis can be accelerated by transduction of non-MYC oncogenes, leading to dual addiction to MYC and the non-MYC oncogenes. Wang et al. (2004) first established the concept of MYC-mediated synthetic lethality (MYC-SL). MYC overexpression sensitized cells to TRAILand DR5-agonist-induced apoptosis. This suggests that MYC-dependent tumor cells may be killed by targeting partner oncogenes of MYC. Many small molecule inhibitors (SMIs) have been proven to induce MYC-SL by targeting AUK-B, Brd4, CDK1, CHK1, MCL-1, the mTOR/4E-BP1/eIF4E pathway, and PIM1/2. Compared with conventional treatment approaches, SMI-induced MYC-SL displays highly selective anticancer activity and much lower cytotoxicity to normal cells. SMI-induced MYC-SL can reverse eIF4F- and PIM2-induced multiple chemoresistance. The combination of an SMI with chemotherapeutic agents can elevate chemotherapy efficacy by enhancing chemosensitivity. This combination will be a promising novel approach to treating MYC-dependent tumors by inducing MYC-SL.

Nanotechnology has revolutionized fundamental opportunities for higher specific drug delivery with minimum side effects. Since its inception, the goal of nanotechnology has been to advance effective and reliable systems for precise anti-cancer therapy and diagnosis. To accomplish this goal, bio-conjugation strategies of therapeutic agents loaded nanoparticles with monoclonal antibodies or their analogues have demonstrated a targeted approach both in vitro and in vivo. In this review, we primarily focus on the specific recognition of HER2 receptors of HER2 overexpressed tumor cells, and evaluate anti-HER2 monoclonal antibody as an effective tool for active targeting. Currently, a variety of nanoparticle systems are under both preclinical and clinical trials for targeting to HER2 positive breast cancer. Different nanotechnology scaffolds including liposomes, dendrimers, micelles, polymeric and inorganic nanoparticles that have higher flexibility for macromolecular synthesis and versatile functionalizing properties have been reviewed in this study. Continuing advances in anti-HER2 functionalized nanoparticles have good potential to lead to the development of nano-therapy against HER2 positive breast cancer.