Zakir Khan

Survivin, a molecular target for therapeutic interventions in squamous cell carcinoma

Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.

The intrarenal generation of angiotensin II is required for experimental hypertension

Hypertension is a major risk factor for cardiovascular disease. While the cause of hypertension is multifactorial, renal dysregulation of salt and water excretion is a major factor. All components of the renin-angiotensin system are produced locally in the kidney, suggesting that intrarenal generation of angiotensin II plays a key role in blood pressure regulation. Here, we show that two mouse models lacking renal angiotensin converting enzyme (ACE) are protected against angiotensin II and l-NAME induced hypertension. In response to hypertensive stimuli, mice lacking renal ACE do not produce renal angiotensin II. These studies indicate that the intrarenal renin-angiotensin system works as an entity separate from systemic angiotensin II generation. Renal ACE appears necessary for experimental hypertension.

Growth inhibition and chemo-radiosensitization of head and neck squamous cell carcinoma (HNSCC) by survivin-siRNA lentivirus.

BACKGROUNDnSurvivin expression is often associated with aggressive tumor behavior and therapy resistance. In this study, we investigated the effect of survivin knockdown by survivin-siRNA lentiviral vector (Svv-Lent) on the response of HNSCC to chemo-radiotherapy, tumor growth and metastasis.nnnMETHODSnFour human HNSCC (OSC19, Cal27, Cal33 and FaDu) and one normal HOK cell lines were included in the study, and survivin knockdown was achieved with Svv-Lent treatment. Cell proliferation and apoptosis were measured by MTT and TUNEL assay, respectively. Transwell assays were performed to measure in vitro cell migration and matrigel invasion. Xenograft tumors were developed in nude mice by injecting Cal27 cells subcutaneously and following tail-vein injection of lung and liver metastasis.nnnRESULTSnKnockdown of survivin significantly suppressed HNSCC cell proliferation and induced apoptosis in vitro. Survivin inhibition could also significantly reduce in vitro cell migration and matrigel invasion that might be due to inactivation of matrix metalloproteinases. In vivo studies showed significant repression of Cal27 xenograft tumor growth and tissue metastasis leading to improvement in mice survival in the Svv-Lent treated group compared to controls. Our data indicated that survivin expression in HNSCC cells contributed to chemo-radioresistance, and its down-regulation increased anti-cancer effects of paclitaxel, cisplatin and radiation.nnnCONCLUSIONSnOur findings suggest that sustained survivin expression facilitates HNSCC tumor growth and confers resistance to chemo-radiotherapy. Svv-Lent therapy may be able to enhance the cytotoxic effect of commonly used anticancer drugs such as cisplatin and paclitaxel, and radiotherapy that could provide a promising strategy for the effective control of resistant head and neck cancer.

Colorectal cancer-inflammatory bowel disease nexus and felony of Escherichia coli

Colorectal cancer (CRC) has a multifactorial etiology. Although the exact cause of CRC is still elusive, recent studies have indicated microbial involvement in its etiology. Escherichia coli has emerged as an important factor in CRC development since the bacterium can cause changes in the gut that lead to cancerous transformation. A number of studies indicate that chronic inflammation induced by microorganisms, including E. coli, during inflammatory bowel disease (IBD) predisposes an individual to CRC. The evidence that support the role of E. coli in the etiology of CRC, through IBD, is not limited only to chronic inflammation. The growth of E. coli as an intracellular pathogen during IBD and CRC enable the bacteria to modulate the host cell cycle, induce DNA damage and accumulate mutations. These are some of the contributing factors behind the etiology of CRC. The present article considers the current status of the involvement of E. coli, through IBD, in the etiology of CRC. We discuss how intracellular E. coli infection can cause changes in the gut that can eventually lead to cellular transformation. In addition, the recent management strategies that target E. coli for prevention of CRC are also discussed.

Angiotensin-converting enzyme enhances the oxidative response and bactericidal activity of neutrophils

Angiotensin-converting enzyme (ACE) inhibitors are widely used to reduce blood pressure. Here, we examined if an ACE is important for the antibacterial effectiveness of neutrophils. ACE knockout mice or mice treated with an ACE inhibitor were more susceptible to bacterial infection by methicillin-resistant Staphylococcus aureus (MRSA). In contrast, mice overexpressing ACE in neutrophils (NeuACE mice) have increased resistance to MRSA and better in vitro killing of MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae ACE overexpression increased neutrophil production of reactive oxygen species (ROS) following MRSA challenge, an effect independent of the angiotensin II AT1 receptor. Specifically, as compared with wild-type (WT) mice, there was a marked increase of superoxide generation (>twofold, P < .0005) in NeuACE neutrophils following infection, whereas ACE knockout neutrophils decreased superoxide production. Analysis of membrane p47-phox and p67-phox indicates that ACE increases reduced NAD phosphate oxidase activity but does not increase expression of these subunits. Increased ROS generation mediates the enhanced bacterial resistance of NeuACE mice because the enhanced resistance is lost with DPI (an inhibitor of ROS production by flavoenzymes) inhibition. NeuACE granulocytes also have increased neutrophil extracellular trap formation and interleukin-1β release in response to MRSA. In a mouse model of chemotherapy-induced neutrophil depletion, transfusion of ACE-overexpressing neutrophils was superior to WT neutrophils in treating MRSA infection. These data indicate a previously unknown function of ACE in neutrophil antibacterial defenses and suggest caution in the treatment of certain individuals with ACE inhibitors. ACE overexpression in neutrophils may be useful in boosting the immune response to antibiotic-resistant bacterial infection.

Angiotensin-converting enzyme in innate and adaptive immunity

Angiotensin-converting enzyme (ACE) — a zinc-dependent dicarboxypeptidase with two catalytic domains — plays a major part in blood pressure regulation by converting angiotensin I to angiotensin II. However, ACE cleaves many peptides besides angiotensin I and thereby affects diverse physiological functions, including renal development and male reproduction. In addition, ACE has a role in both innate and adaptive responses by modulating macrophage and neutrophil function — effects that are magnified when these cells overexpress ACE. Macrophages that overexpress ACE are more effective against tumours and infections. Neutrophils that overexpress ACE have an increased production of superoxide, which increases their ability to kill bacteria. These effects are due to increased ACE activity but are independent of angiotensin II. ACE also affects the display of major histocompatibility complex (MHC) class I and MHC class II peptides, potentially by enzymatically trimming these peptides. Understanding how ACE expression and activity affect myeloid cells may hold great promise for therapeutic manipulation, including the treatment of both infection and malignancy.

Renal tubular ACE-mediated tubular injury is the major contributor to microalbuminuria in early diabetic nephropathy

Diabetic nephropathy is a major cause of end-stage renal disease in developed countries. While angiotensin-converting enzyme (ACE) inhibitors are used to treat diabetic nephropathy, how intrarenal ACE contributes to diabetic renal injury is uncertain. Here, two mouse models with different patterns of renal ACE expression were studied to determine the specific contribution of tubular vs. glomerular ACE to early diabetic nephropathy: it-ACE mice, which make endothelial ACE but lack ACE expression by renal tubular epithelium, and ACE 3/9 mice, which lack endothelial ACE and only express renal ACE in tubular epithelial cells. The absence of endothelial ACE normalized the glomerular filtration rate and endothelial injury in diabetic ACE 3/9 mice. However, these mice developed tubular injury and albuminuria and displayed low renal levels of megalin that were similar to those observed in diabetic wild-type mice. In diabetic it-ACE mice, despite hyperfiltration, the absence of renal tubular ACE greatly reduced tubulointerstitial injury and albuminuria and increased renal megalin expression compared with diabetic wild-type and diabetic ACE 3/9 mice. These findings demonstrate that endothelial ACE is a central regulator of the glomerular filtration rate while tubular ACE is a key player in the development of tubular injury and albuminuria. These data suggest that tubular injury, rather than hyperfiltration, is the main cause of microalbuminuria in early diabetic nephropathy.

Overexpression of angiotensin-converting enzyme in myelomonocytic cells enhances the immune response

Angiotensin-converting enzyme (ACE) converts angiotensin I to the vasoconstrictor angiotensin II and thereby plays an important role in blood pressure control. However, ACE is relatively non-specific in its substrate specificity and cleaves many other peptides. Recent analysis of mice overexpressing ACE in monocytes, macrophages, and other myelomonocytic cells shows that these animals have a marked increase in resistance to experimental melanoma and to infection by Listeria monocytogenes or methicillin-resistant Staphylococcus aureus (MRSA). Several other measures of immune responsiveness, including antibody production, are enhanced in these animals. These studies complement a variety of studies indicating an important role of ACE in the immune response.

Computational prediction of Escherichia coli proteins host subcellular targeting and their implications in colorectal cancer etiology

Recent evidences indicate potential Escherichia coli involvement in colorectal cancer etiology. Colorectal cancer cells are exclusively colonized by enteroinvasive E. coli, which regulates several factors that can affect colorectal cancer progression in susceptible individuals. Earlier, we predicted nuclear targeting of E. coli proteins and their role in colorectal cancer etiology. In this study, we predict targeting of E. coli proteins in host cell mitochondria and cytoplasm and their role in colorectal cancer. Several important biological processes are regulated in the cell cytoplasm and mitochondria, where the targeting of E. coli proteins may have several possible implications. A total of 87/561 and 315/561 E. coli proteins were found to target host cell mitochondria and cytoplasm respectively. These include several proteins with the ability to influence normal growth behavior. The current article provides an outline for E. coli protein targeting in host cells and suggests that these proteins can contribute to the colorectal cancer etiology through a variety of strategies.

Survivin as a Therapeutic Target in Squamous Cell Carcinoma

Survivin is a universal tumor marker that belongs to inhibitor of apoptosis protein (IAP) family. It is involved in the control of cell cycle and inhibition of apoptosis. As like other cancers, most of the SCCs also overexpress survivin gene. Tumors overexpressing survivin generally bear a poor prognosis and are associated with resistance to therapy. The differential expression of survivin in cancer versus normal tissues makes it a useful tool in cancer diagnosis and a promising therapeutic target. Disruption of the survivin induction pathway has resulted in an increase in apoptosis and inhibition of tumor growth. In this chapter, we will discuss recent advances in cancer therapeutics targeting survivin gene.