Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.
We conducted a meta-analysis in order to investigate the relationships between PTEN gene mutations and the prognosis in glioma. The following electronic databases were searched for relevant articles without any language restrictions: Web of Science (1945 ~ 2013), the Cochrane Library Database (Issue 12, 2013), PubMed (1966 ~ 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013). Meta-analyses were conducted using the STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Hazard ratio (HR) with its corresponding 95 % confidence interval (95%CI) was calculated. Six independent cohort studies with a total of 357 glioma patients met our inclusion criteria. Our meta-analysis results indicated that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95%CI = 2.02 ~ 5.30, P < 0.001). Ethnicity-stratified subgroup analysis demonstrated that PTEN gene mutations were closely linked to poor prognosis in glioma among Americans (HR = 3.72, 95%CI = 1.72 ~ 5.73, P < 0.001), while similar correlations were not observed among populations in Sweden, Italy, and Malaysia (all P > 0.05). Our meta-analysis provides direct and strong evidences for the speculation of PTEN gene mutations' correlation with poor prognosis of glioma patients.
Effective cancer management depends on early diagnosis and treatment. There are several microRNAs (miRNAs) which are used for detection of various cancers. Cell-free and circulating miRNAs originate from plasma, either from blood cells or endothelial cells. Cell-free and circulating miRNAs are very much important in the diagnosis and prognosis of cancer therapy. Admittedly, biological knowledge of extracellular miRNAs is still at its preliminary level. Recent discoveries of novel cell-free and circulating miRNAs from the body fluids are now being considered as important biomarkers that may help us in the early diagnosis of any cancer. In the present review, we highlight the biogenesis of miRNAs and their current extracellular pattern, the discovery of circulating miRNA, significant advantages, and different profiling techniques. Finally, we discuss the different circulating miRNAs such as miR-21, miR-20a, miR-155, miR‑221, miR-210, miR-218, miR-200-family, miR-141, miR-122, miR-486-5p, miR‑423-5p, miR-29a, and miR-500 for clinical diagnosis of various cancers. The present review may be beneficial for future researches concerned with miRNAs which are used for detection of various cancers.
Topoisomerases are nuclear enzymes that regulate topology of DNA by facilitating the temporary cleavage and ligation cycle of DNA. Among all forms of topoisomerases, TOP-IIA is extensively associated with cell proliferation and therefore is an important therapeutic target in diseases that involved cellular proliferation such as cancers. Nearly half of present-day antitumor regimens contain at least one prescription that act as a topoisomerase inhibitor. Generally, tumor cells show divergent expression of TOP-IIA compared to normal cells. The remarkable expression of TOP-IIA in various carcinomas provides a significant biomarker toward understanding the nature of malignancy. TOP-IIA expression and amplification studies help in diagnosing cancer and to observe the disease progression, overall survival (OS) of patients, and response to therapy. This review highlights the research output and analysis in exploring the standing of TOP-IIA in various carcinomas. As some reports show contradiction within the same field of interest, the outline of that may help to induce researchers for further investigation and clarification. To the best of our knowledge, this is the first overview briefly summarizing the prognostic feature of TOP-IIA in various types of cancer.
Cancer has long been assumed to be a genetic disease. However, recent evidence supports the enigmatic connection of bacterial infection with the growth and development of various types of cancers. The cause and mechanism of the growth and development of prostate cancer due to Mycoplasma hominis remain unclear. Prostate cancer cells are infected and colonized by enteroinvasive M. hominis, which controls several factors that can affect prostate cancer growth in susceptible persons. We investigated M. hominis proteins targeting the nucleus of host cells and their implications in prostate cancer etiology. Many vital processes are controlled in the nucleus, where the proteins targeting M. hominis may have various potential implications. A total of 29/563 M. hominis proteins were predicted to target the nucleus of host cells. These include numerous proteins with the capability to alter normal growth activities. In conclusion, our results emphasize that various proteins of M. hominis targeted the nucleus of host cells and were involved in prostate cancer etiology through different mechanisms and strategies.
As the cellular prion protein (PrP(C)) has been implicated in carcinogenesis, we aimed to investigate the effects of cancer cell-specific PrP(C) overexpression from the invasion, metastasis, and apoptosis aspects, by performing cell motility assays, cell proliferation assays under anchorage-dependent and anchorage-independent conditions, and apoptosis evasion when subjected to multiple anti-cancer drugs. Overexpression of PrP(C) in LS 174T was achieved by stable transfection. PrP(C) overexpression was shown to increase cell proliferation in anchorage-dependent and anchorage-independent manners, as shown by more viable cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, more colonies formed in soft agar assay and increased resistance to anoikis in poly-2-hydroxyethyl methacrylate-coated surface. PrP(C) overexpression also increased cell motility and invasiveness of LS 174T. Cell adhesion to extracellular matrix using collagen- and fibronectin-coated surfaces revealed increased cell attachment in LS 174T cells overexpressing PrP(C). Analysis of apoptotic and necrotic cells by propidium iodide/annexin V-fluorescein isothiocyanate microscopy and 7-amino-actinomycin D/annexin V-phycoerythrin flow cytometry revealed that PrP(C) overexpression attenuated doxorubicin-induced apoptosis. Human apoptosis antibody array with 35 apoptosis-related proteins revealed that three inhibitor of apoptosis proteins (IAPs)-survivin, X-linked inhibitor of apoptosis protein (XIAP), and cellular inhibitor of apoptosis protein-1 (cIAP-1)-were upregulated in LS 174T cells overexpressing PrP(C) in doxorubicin-induced apoptosis. In conclusion, the overexpression of PrP(C) could enhance the invasiveness and survival of LS 174T colorectal cancer cells, indicating that PrP(C) plays a role in colorectal cancer biology.
γ-synuclein, a neuronal protein of the synuclein family, is involved in carcinogenesis. To investigate its role in colorectal cancer carcinogenesis, we overexpressed γ-synuclein in LS 174T colon adenocarcinoma cell line (termed LS 174T-γsyn). When compared with untransfected/mock transfectants, LS 174T-γsyn had higher mobility in scratch wound assay, tend to scatter more in cell-scattering assay, and had enhanced lamellipodia and filopodia formation in cell-spreading assay. Enhanced adhesion of LS 174T-γsyn to fibronectin and collagen and significantly higher proliferation rate showed that γ-synuclein was able to increase extracellular matrix interaction and promoted proliferation of LS 174T. Higher invasiveness of LS 174T-γsyn was evidenced by enhanced invasion to the bottom of the basement membrane in Boyden chamber assay. However, LS 174T-γsyn were significantly more vulnerable to doxorubicin, vincristine and hydrogen peroxide insults, via apoptotic cell death. LS 174T-γsyn also had reduced anchorage-independent growth as shown by reduced colony formation and reduced anoikis resistance. We found that overexpression of γ-synuclein confers both pro-invasive and doxorubicin-mediated pro-apoptotic properties to LS 174T, where the former was mediated through enhanced cyclic adenosine monophosphate response element binding protein (CREB) phosphorylation, while the latter involved hepatocyte growth factor (HGF) downregulation and subsequent downstream signalling pathways possibly involving extracellular signal-regulated kinases (ERK)1/2, p38α, c-Jun N-terminal kinase (JNK) pan and Signal Transducers and Activators of Transcription (STATs). This unexpected contrasting finding as compared to other similar studies on colon cancer cell lines might be correlated with the degree of tumour advancement from which the cell lines were derived from.
With great interest, we read the article "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis" (by Xiao et al. Tumor Biol 35(7):6687-6693, 2014), which has reached important conclusions that the phosphatase and tensin homolog (PTEN) gene mutations were closely related to poor prognosis of glioma patients. Through quantitative analysis, the investigators (Xiao WZ et al.) showed that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95 % CI = 2.02∼5.30, P 0.05). The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise.
Cervical cancer is a common malignancy which poses a significant health burden among women, especially those living in the developing countries. Although human papillomavirus (HPV) infection has been unequivocally implicated in the etiopathogenesis of the cancer, it alone is not adequate to contribute to the malignant transformation of cervical cells. Most HPV infections regress spontaneously, and only a small proportion of women have persistent infections which eventually lead to malignancy. This suggests that interplays between HPV infection and other cofactors certainly exist during the process of cervical carcinogenesis, which synergistically contribute to the differential susceptibility of an individual to the malignancy. Undoubtedly, host genetic factors represent a major element involved in such a synergistic interaction, and accumulating evidence suggests that polymorphisms in apoptosis-related genes play an important role in the genetic susceptibility to cervical cancer. This review consolidates the recent literatures on the role of common polymorphisms in apoptosis-related genes in genetic susceptibility to cervical cancer.
Corroborating evidence related to the role of aberrations on one-carbon metabolism (OCM) genes has been inconsistent. We evaluated the association between polymorphisms in 12 single nucleotide polymorphisms (SNPs) in 8 OCM genes (CBS, FPGS, FTHFD, MTRR, SHMT1, SLC19A1, TCN1, and TYMS), and non-Hodgkin lymphoma (NHL) risk in a multi-ethnic population which includes Malay, Chinese and Indian ethnic subgroups. Cases (N = 372) and controls (N = 722) were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects showed a significantly enhanced NHL risk for CBS Ex9 + 33C > T (T versus C: OR 1.55, 95% CI 1.22-1.96, P = 0.0003), CBS Ex18-319G > A (A versus G: OR 1.15, 95% CI 1.14-1.83; P = 0.002), SHMT1 Ex12 + 236 T > C (T versus C: OR 1.44, 95% CI 1.15-1.81, P = 0.002), and TYMS Ex8 + 157C > T (T versus C: OR 1.29, 95% CI 1.06-1.57, P = 0.01). Haplotype analysis for CBS SNPs showed a significantly decreased risk of NHL in subjects with haplotype CG (OR 0.69, 95% CI 0.56-0.86, P = <0.001). The GG haplotype for the FTHFD SNPs showed a significant increased risk of NHL (OR 1.40, 95% CI 1.12-1.76, P = 0.002). For the TYMS gene, haplotype CAT at TYMS (OR 0.67, 95% CI 0.49-0.90, P = 0.007) was associated with decreased risk of NHL, while haplotype TAC (OR 1.29, 95% CI 1.05-1.58, P = 0.01) was found to confer increased risk of NHL. Our study suggests that variation in several OCM genes (CBS, FTHFD, SHMT1, TCN1, and TYMS) may influence susceptibility to NHL.
Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.
The process of angiogenesis is quite well-known nowadays. Some medicines and extracts affecting this process are already used routinely in supporting the conventional treatment of many diseases that are considered angiogenic such as cancer. However, we must be aware that the area of currently used drugs of this type is much narrower than the theoretical possibilities existing in therapeutic angiogenesis. Plant substances are a large and diverse group of compounds that are found naturally in fruits, vegetables, spices, and medicinal plants. They also have different anticancer properties. The aim of this literature review article is to present the current state of knowledge concerning the molecular targets of tumor angiogenesis and the active substances (polyphenols, alkaloids, phytohormones, carbohydrates, and terpenes) derived from natural sources, whose activity against cancer angiogenesis has been confirmed.
Over the last few years, microRNAs (miRNA)-controlled cancer stem cells have drawn enormous attention. Cancer stem cells are a small population of tumor cells that possess the stem cell property of self-renewal. Recent data shows that miRNA regulates this small population of stem cells. In the present review, we explained different characteristics of cancer stem cells as well as miRNA regulation of self-renewal and differentiation in cancer stem cells. We also described the migration and tumor formation. Finally, we described the different miRNAs that regulate various types of cancer stem cells, such as prostate cancer stem cells, head and neck cancer stem cells, breast cancer stem cells, colorectal cancer stem cells, lung cancer stem cells, gastric cancer stem cells, pancreatic cancer stem cells, etc. Extensive research is needed in order to employ miRNA-based therapeutics to control cancer stem cell population in various cancers in the future.
Studies have shown an association between ARID5B gene polymorphisms and childhood acute lymphoblastic leukemia. However, the association between ARID5B variants and acute lymphoblastic leukemia among the Arab population still needs to be studied. The aim of this study was to investigate the association between ARID5B variants with acute lymphoblastic leukemia in Yemeni children. A total of 14 ARID5B gene single nucleotide polymorphisms (SNPs) were genotyped in 289 Yemeni children, of whom 136 had acute lymphoblastic leukemia and 153 were controls, using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Using logistic regression adjusted for age and gender, the risks of acute lymphoblastic leukemia were presented as odds ratios and 95% confidence intervals. We found that nine SNPs were associated with acute lymphoblastic leukemia under additive genetic models: rs7073837, rs10740055, rs7089424, rs10821936, rs4506592, rs10994982, rs7896246, rs10821938, and rs7923074. Furthermore, the recessive models revealed that six SNPs were risk factors for acute lymphoblastic leukemia: rs10740055, rs7089424, rs10994982, rs7896246, rs10821938, and rs7923074. The gender-specific impact of these SNPs under the recessive genetic model revealed that SNPs rs10740055, rs10994982, and rs6479779 in females, and rs10821938 and rs7923074 in males were significantly associated with acute lymphoblastic leukemia risk. Under the dominant model, SNPs rs7073837, rs10821936, rs7896246, and rs6479778 in males only showed striking association with acute lymphoblastic leukemia. The additive model revealed that SNPs with significant association with acute lymphoblastic leukemia were rs10821936 (both males and females); rs7073837, rs10740055, rs10994982, and rs4948487 (females only); and rs7089424, rs7896246, rs10821938, and rs7923074 (males only). In addition, the ARID5B haplotype block (CGAACACAA) showed a higher risk for acute lymphoblastic leukemia. The haplotype (CCCGACTGC) was associated with protection against acute lymphoblastic leukemia. In conclusion, our study has shown that ARID5B variants are associated with acute lymphoblastic leukemia in Yemeni children with several gender biases of ARID5B single nucleotide polymorphisms reported.
Xanthones are phytochemical compounds found in a number of fruits and vegetables. Characteristically, they are noted to be made of diverse properties based on their biological, biochemical, and pharmacological actions. Accordingly, the apoptosis mechanisms induced by beta-mangostin, a xanthone compound isolated from Cratoxylum arborescens in the human promyelocytic leukemia cell line (HL60) in vitro, were examined in this study. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was done to estimate the cytotoxicity effect of β-mangostin on the HL60 cell line. Acridine orange/propidium iodide and Hoechst 33342 dyes and Annexin V tests were conducted to detect the apoptosis features. Caspase-3 and caspase-9 activities; reactive oxygen species; real-time polymerase chain reaction for Bcl-2, Bax, caspase-3, and caspase-9 Hsp70 genes; and western blot for p53, cytochrome c, and pro- and cleavage-caspase-3 and caspase-9 were assessed to examine the apoptosis mechanism. Cell-cycle analysis conducted revealed that β-mangostin inhibited the growth of HL60 at 58 µM in 24 h. The administration of β-mangostin with HL60 caused cell morphological changes related to apoptosis which increased the number of early and late apoptotic cells. The β-mangostin-catalyzed apoptosis action through caspase-3, caspase-7, and caspase-9 activation overproduced reactive oxygen species which downregulated the expression of antiapoptotic genes Bcl-2 and HSP70. Conversely, the expression of the apoptotic genes Bax, caspase-3, and caspase-9 were upregulated. Meanwhile, at the protein level, β-mangostin activated the formation of cleaved caspase-3 and caspase-9 and also upregulated the p53. β-mangostin arrested the cell cycle at the G0/G1 phase. Overall, the results for β-mangostin showed an antiproliferative effect in HL60 via stopping the cell cycle at the G0/G1 phase and prompted the intrinsic apoptosis pathway.