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Multimodal therapeutic agents based on novel nanomaterials for multidrug resistance have attracted increasing attention in cancer therapy. In this study, we describe the construction of a programmed mesoporous silica-capped gold nanorod covered with nano-selenium overcoat (Se@Au@mSiO 2 ) nanoparticles as a multifunctional nanoplatform to incorporate materials with specific chemotherapeutic, chemoprevention, and photoablation/hyperthermia functions that collectively contribute to enhance anticancer efficacy in multidrug-resistant breast cancer. The triplecombination-based nanosized Se@Au@mSiO 2 /DOX effectively accumulates in the tumor and the release of the therapeutic cargo could be remotely manipulated by mild near-infrared (NIR) irradiation. Se@Au@mSiO 2 /DOX notably enhances the cell killing effect through induction of cell apoptosis. In addition, Se@Au@mSiO 2 /DOX inhibits tumor cell growth through cell cycle arrest and induction of apoptosis via suppression of the Src/FAK/AKT signaling pathways. Synergistic Se-photothermal-chemotherapy combination exhibits significant tumor growth suppression and delayed tumor progression in vivo. Immunohistochemistry analysis shows elevated numbers of caspase-3 and PARPimmunolabeled cells and decreased Ki-67 + and CD31 + cancer cells in the tumor mass. No noticeable signs of organ damage or toxicity are observed after treatment with Se@Au@mSiO 2 /DOX (NIR+), which is further supported by hematology and biochemical analyses. Thus, Se@Au@mSiO 2 /DOX has potential for the clinical treatment of metastatic breast cancers with little or no adverse effects.

Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK) plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+) supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa), its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+) levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain) in a dose-dependent manner. Phosphorylated FAK (p-FAK) was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer.

The roles of mitochondrial dysfunction in carcinogenesis remain largely unknown. The effects of PTEN‐induced putative kinase 1 (PINK1)‐dependent mitophagy on the pathogenesis of multiple myeloma (MM) are determined. The levels of the PINK1‐dependent mitophagy markers PINK1 and parkin RBR E3 ubiquitin protein ligase (PARK2) in CD138+ plasma cells are reduced in patients with MM and correlate with clinical outcomes in myeloma patients. Moreover, the induction of PINK1‐dependent mitophagy with carbonylcyanide‐m‐chlorophenylhydrazone (CCCP) or salinomycin, or overexpression of PINK1 leads to inhibition of transwell migration, suppression of myeloma cell homing to calvarium, and decreased osteolytic bone lesions. Furthermore, genetic deletion of pink1 accelerates myeloma development in a spontaneous X‐box binding protein‐1 spliced isoform (XBP‐1s) transgenic myeloma mouse model and in VK*MYC transplantable myeloma recipient mice. Additionally, treatment with salinomycin shows significant antimyeloma activities in vivo in murine myeloma xenograft models. Finally, the effects of PINK1‐dependent mitophagy on myeloma pathogenesis are driven by the activation of the Mps one binder kinase activator (MOB1B)‐mediated Hippo pathway and the subsequent downregulation of Yes‐associated protein (YAP)/transcriptional co‐activator with PDZ‐binding motif (TAZ) expression. These data provide direct evidence that PINK1‐dependent mitophagy plays a critical role in the pathogenesis of MM and is a potential therapeutic target.

Abstract. Aim: To investigate the possibility of enhancing an anti-metastatic effect of 5-fluorouracil (5-FU) on colorectal cancer (CRC) cells by combining it with continuous calcium supplementation. Materials and Methods: Optimal doses of 5-FU with/without lactate salt (CaLa) were determined via clonogenicity and 3- (4,5-dimethylthiazol-2-yl Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancerrelated death in both men and women (1). According to the estimates of the Global Cancer Control (GLOBOCAN) project, nearly 1.4 million people worldwide were diagnosed with CRC in 2012, with the Republic of Korea displaying the highest incidence rates, followed by Slovakia and Hungary (2).CRC that has grown into the wall can penetrate blood or lymph vessels; typically, cancer cells first invade nearby lymph nodes, and then spread to other parts of the body, such as the liver or lung (1, 3). Approximately 150,000 new cases are diagnosed each year, with about 20% of them already displaying metastases (2). Metastatic CRC is often harder to treat and tends to have a poor treatment outcome. As a result, patients with metastatic CRC have a low 5-year survival rate of about 11% (1, 2).In patients newly diagnosed with CRC, 5-fluorouracil (5-FU) is usually administered intravenously in combination with a second drug called leucovorin (4). Moreover, most patients with newly-diagnosed metastatic CRC undergo surgery after receiving chemotherapy with 5-FU (5). Other combinatorial treatments have also been tested for first-line chemotherapy of metastatic CRC, where a targeted drug, such as bevacizumab or cetuximab, is co-administered to increase the efficiency of 5-FU (6). However, these regimens suffer from increased toxicity, and cause symptoms such as neutropenia, severe diarrhea, and vomiting (7). Moreover, 5-FU is not an effective treatment strategy because it only delays micrometastasis. The mechanism through which 5-FU acts on CRC metastases remains unclear (8).Focal adhesion kinase (FAK), a protein kinase involved in cellular adhesion, is activated in several types of advancedstage cancer. In CRC cells, phosphorylation of FAK occurs on multiple residues, and overexpression of FAK has been detected in liver metastases of CRC (9). FAK has been implicated in the regulation of the expression of genes 103 Τhis article is freely accessible online.