Sadanandan E Velu

University of Alabama at Birmingham | UAB · Department of Chemistry

Background and Purpose Gastrointestinal tumours overexpress voltage‐gated calcium (CaV3) channels (CaV3.1, 3.2 and 3.3). CaV3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti‐tumour properties and inhibits CaV3 currents. A systematic study was performed on gossypol...

This review focuses on the expression and function of voltage-gated sodium channel subtype NaV1.7 in various cancers and explores its impact on the metastasis driving cell functions such as proliferation, migration, and invasiveness. An overview of its structural characteristics, drug binding sites, inhibitors and their likely mechanisms of action...

The tenacious biofilms formed by Streptococcus mutans are resistant to conventional antibiotics and current treatments. There is a growing need for novel therapeutics that selectively inhibit S. mutans biofilms while preserving the normal oral microenvironment. Previous studies have shown that increased levels of cyclic di-AMP, an important seconda...

We designed and synthesized analogues of a previously identified biofilm inhibitor IIIC5 to improve solubility, retain inhibitory activities, and to facilitate encapsulation into pH-responsive hydrogel microparticles. The optimized lead compound HA5 showed improved solubility of 120.09 μg/mL, inhibited Streptococcus mutans biofilm with an IC50 valu...

Simple Summary Despite the recent advances in the diagnosis and treatment of medullary thyroid cancer (MTC), it remains an understudied cancer type and continues to disproportionately contribute to thyroid-cancer-related mortality. In this manuscript, we report, for the first time, the overexpression of voltage-gated sodium channel subtype NaV1.7 i...

Accumulating evidence has demonstrated that the overexpression of and the loss of tumor suppressor genes contribute to the aggressiveness, poor prognosis, and poor response to treatment associated with advanced cancer. Overexpression and activation of the MDM2 and NFAT1 oncogenes frequently occur in human cancer and is associated with invasive and...

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including C...

The production of noncanonical mRNA transcripts is associated with cell transformation. Driven by our previous findings on the sensitivity of T cell acute lymphoblastic leukemia (T-ALL) cells to SF3B1 inhibitors, we identified that SF3B1 inhibition blocks T-ALL growth in vivo with no notable associated toxicity. We also revealed protein stabilizati...

Additional prognostic and therapeutic biomarkers effective across different histological types of sarcoma are needed. Herein we evaluate expression of TAZ and YAP, the p53-MDM2 axis, and RABL6A, a novel oncoprotein with potential ties to both pathways, in sarcomas of different histological types. Immunohistochemical staining of a tissue microarray...

Voltage-gated sodium (NaV) channels, initially characterized in excitable cells, have been shown to be aberrantly expressed in non-excitable cancer tissues and cells from epithelial origins such as in breast, lung, prostate, colon, cervix, while they are not expressed in cognate non-cancer tissues. Their activity was demonstrated to promote aggress...

The oncogenic human herpesviruses Epstein–Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are the causative agents of multiple malignancies. A hallmark of herpesviruses is their biphasic life cycle consisting of latent and lytic infection. In this study, we identified that cellular nonsense-mediated decay (NMD), an evolutionaril...

Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mu...

In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this...

Non-melanoma skin cancer is one of the major ailments in the United States. Effective drugs that can cure skin cancers are limited. Moreover, the available drugs have toxic side effects. Therefore, skin cancer drugs with less toxic side effects are urgently needed. To achieve this goal, we focused our work on identifying potent lead compounds from...

Hepatocellular carcinoma (HCC) poses a major public health problem worldwide and novel, effective therapeutic approaches for this devastating disease are urgently needed. The overexpression or activation of the MDM2 oncogene frequently occurs in HCC and is linked to cancer growth, poor survival, metastasis, and resistance to treatment. We have hypo...

Medullary thyroid cancer (MTC) is a type of neuroendocrine cancer (NE) with increasing incidence worldwide. Compared with well-differentiated thyroid cancers, distant metastases are more commonly observed in MTC patients, ranging from 7-23%. The inability to treat metastatic MTC contributes to a decreased patient survival rate. Currently, at least...

Medullary thyroid cancer (MTC) is a type of neuroendocrine cancer (NE) with increasing incidence worldwide. Compared with well-differentiated thyroid cancers, distant metastases are more commonly observed in MTC patients, ranging from 7-23%. The inability to treat metastatic MTC contributes to a decreased patient survival rate. Currently, at least...

p>Hepatocellular carcinoma (HCC) poses a major public health problem worldwide and novel, effective therapeutic approaches for this devastating disease are urgently needed. The overexpression or activation of the MDM2 oncogene frequently occurs in HCC and is linked to cancer growth, poor survival, metastasis, and resistance to treatment. We have hy...

Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins frequently occur in pancreatic cancer. Most MDM2 inhibitors under development target MDM2–p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer. Some available compounds i...

Purpose: Elevation of L-2-hydroxylgutarate (L-2-HG) in renal cell carcinoma (RCC) is due in part to reduced expression of L-2-HG dehydrogenase (L2HGDH). However, the contribution of L-2-HG to renal carcinogenesis and insight into the biochemistry and targets of this small molecule remains to be elucidated. Experimental design: Genetic and pharma...

Removal of oral biofilms involves the use of broad-spectrum antimicrobials, which eradicate both pathogenic and protective oral commensal species. Ideal therapeutics for dental caries should be able to selectively inhibit pathogenic biofilms caused by Streptococcus mutans. S. mutans extracellular glucosyltransferases (Gtfs), particularly GtfB and G...

Background: The D-enantiomer of 2-hydroxygultarate (D-2HG), along with fumarate and succinate, are considered oncometabolites that promote tumorigenesis. Our lab has reported elevated levels of the L-enantiomer of 2-hydroxyglutare (L-2HG) in clear cell renal cell carcinoma (ccRCC), in part due to reduced expression of the enzyme L-2HG dehydrogenase...

Voltage-gated sodium channels (VGSC) are a well-established drug target for anti-epileptic, anti-arrhythmic and pain medications due to their presence and the important roles that they play in excitable cells. Recently, their presence has been recognized in non-excitable cells such as cancer cells and their overexpression has been shown to be assoc...

Murrayaquinones A–D is a group of four bioactive carbazole-1,4-dione natural products isolated from the root bark of the plant Murraya eucrestifolia hayata. Murrayaquinone is synthesized in five steps starting from the commercially available 2,4,5-trimethoxybenzaldehyde with an overall yield of 45%. The novelty of this murrayaquinone synthesis is i...

Streptococcus mutans employs a key virulence factor, three glucosyltransferase (GtfBCD) enzymes to establish cariogenic biofilms. Therefore, the inhibition of GtfBCD would provide anti-virulence therapeutics. Here a small molecule library of 500,000 small molecule compounds was screened in silico against the available crystal structure of the GtfC...

Statement of significance: Many potent anticancer drugs are hydrophobic and lack tumor selectivity, which limits their application in cancer therapy. Although cubical hydrogels of poly(methacrylic acid) exhibit excellent biocompatibility and versatility, they have not been investigated for hydrophobic drug delivery due to poor mechanical stability...

Bisphosphonates are standard treatments for bone metastases. When given in the adjuvant setting, they reduce breast cancer mortality and recurrence in bone but only among post-menopausal patients. Optimal drug use would require biomarker-based patient selection. Such biomarkers are not yet in clinical use. Based on the similarities in inflammatory...

_Streptococcus mutans_ has been implicated as the major etiological agent in the initiation and the development of dental caries due to its robust capacity to form tenacious biofilms. Ideal therapeutics for this disease will aim to selectively inhibit the biofilm formation process while preserving the natural bacterial flora of the mouth. Several s...

Natural products and their derivatives represent a rich source for the discovery and development of new cancer therapeutic drugs. Bioactive components derived from natural sources including marine compounds have been shown to be effective agents in the clinic or in preclinical settings. In the present review, we present a story of discovery, synthe...

The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotec...

Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate...

Supplementary material Figure S1: Basal ECAR of MB231 and MCF10A cells in response to BTPP or IBTP. MB231 cells were treated with vehicle (EtOH), IBTP (0.01-10 µM), or BTPP (0.01-10 µM) for 24 h and basal ECAR was measured in parallel with the mitochondrial stress tests described in Fig. 1, Fig. 2. Panel A: Dose response of IBTP or BTPP on basal EC...

Supplementary material Figure S2: Adenine nucleotide levels replotted as % of control. Adenine nucleotide levels measured by HPLC analysis from Fig. 5 are replotted, and values are expressed as % of vehicle control at each time point ±SEM obtained from 3 separate experiments. *P<0.05 compared to vehicle and #P<0.05 IBTP compared to BTPP.

Supplementary material Figure S3: Validation of IBTP effects on GAC protein levels. MB231 cells were treated with IBTP (10 µM) or BTPP (10 µM) for the indicated times (4-24h), or were treated for 24 h followed by removal of the treatment and recovery for 24 or 48 h. Panel A: Image from Western blot analysis using a monoclonal anti-GAC/KGA/GAM antib...

Supplementary material Figure S4: Time course of TPP adduct formation. MB231 cells were treated with either IBTP (10 µM) or BTPP (10 µM) for the indicated times. Cell lysates were prepared and protein adducts were visualized by Western blot analysis using an antibody directed against the TPP moiety (1:3000). Open arrows indicated by the ˃ symbol sh...

In this study, we present data indicating a robust and specific domain interaction between the CFTR first cytosolic loop (CL1) and nucleotide binding domain 1 (NBD1) that allows ion transport to proceed in a regulated fashion. We used co-precipitation and ELISA to establish the molecular contact and showed binding kinetics were not altered by the c...

Mitochondrial metabolism is an essential biological process that generates both energy and signaling mediators, and perturbations by increased oxidative stress can cause metabolic dysfunction which has been shown to play an important role in pathologies such as cardiovascular disease, neurodegenerative disorders, and cancer. Our recent work demonst...

The ocean continues to provide a plethora of unique scaffolds capable of remarkable biological applications. A large number of pyrroloiminoquinone alkaloids, including discorhabdins, epinardins, batzellines, makaluvamines, and veiutamine, have been isolated from various marine organisms. A class of pyrroloiminoquinone-related alkaloids, known as bi...

Traditionally, natural products have played a major role in drug discovery by serving as the source of earliest medicine. In spite of the scientific advancements and the promise of alternative drug discovery strategies in the recent decades, there is still a shortage of drugs leading to clinical trials for various diseases. Calothrixin B and its N-...

We have recently designed and synthesized several novel iminoquinone anticancer agents that have entered preclinical development for the treatment of human cancers. Herein we developed and validated a quantitative HPLC-MS/MS analytical method for one of the lead novel anticancer makaluvamine analog, TCBA-TPQ, and conducted a pharmacokinetic study i...

Here, we report the chemotherapeutic effect of honokiol, a phytochemical from Magnolia plant, on human head and neck squamous cell carcinoma (HNSCC). Treatment of HNSCC cell lines from different sub-sites, SCC-1 (oral cavity), SCC- 5 (larynx), OSC-19 (tongue) and FaDu (pharynx) with honokiol inhibited their cell viability, which was associated with...

Despite advances in screening and treatment over the past several years, breast cancer remains a leading cause of cancer-related death among women in the United States. A major goal in breast cancer treatment is to develop safe and clinically useful therapeutic agents that will prevent the recurrence of breast cancers after front-line therapeutics...

We undertook an unbiased metabolomics profile of clear cell renal cell carcinoma (ccRCC), the most common histological subtype, to gain deeper insight into the metabolic basis of this disease. Here, we demonstrate elevations of the metabolite 2-hydroxyglutarate (2HG) in kidney cancer. Elevation of 2HG, specifically the D- enantiomer, has been linke...

Streptococcus mutans is a key etiological agent in the formation of dental caries. The major virulence factor is its ability to form biofilms. Inhibition of S. mutans biofilms offers therapeutic prospects for the treatment and the prevention of dental caries. In this study, 14 analogs of makaluvamine, a marine alkaloid, were evaluated for their ant...

Unlabelled: Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)-dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of...

Bioactive indolo[3,2-j]phenanthridine alkaloids, calothrixin B and its N-oxide derivative calothrixin A have been synthesized via an oxidative free radical reaction. calothrixin B is generated from the commercially available 2,4,5-trimethoxybenzaldehyde in only 7 steps. The key step in this synthesis is the Mn(OAc)3 mediated oxidative free radical...

Pyrroloquinone ring systems are important structural units present in many biologically active molecules including a number of marine alkaloids. For example, they are found in a series of marine metabolites, such as tsitsikammamines, zyzzyanones, wakayin, and terreusinone. Several of these alkaloids have exhibited antimicrobial, antimalarial, antif...

Zyzzyanones A-D is a group of biologically active marine alkaloids isolated from Australian marine sponge Zyzzya fuliginosa. They contain a unique bispyrroloquinone ring system as the core structure. The first total synthesis of all four zyzzyanones is described here. The synthesis of these alkaloids started from a previously known 6-benzylamino in...

Identification and validation of molecular targets are considered as a key element in new drug discovery and development. We have recently demonstrated that a novel synthetic iminoquinone analog, termed [7-(benzylamino)-1,3,4,8-tetrahydropyrrolo [4,3, 2-de]quinolin-8(1H)-one] (BA-TPQ), has significant anti-breast cancer activity both in vitro and i...

Nonsense suppression therapy is an approach to treat genetic diseases caused by nonsense mutations. This therapeutic strategy pharmacologically suppresses translation termination at Premature Termination Codons (PTCs) in order to restore expression of functional protein. However, the process of Nonsense-Mediated mRNA Decay (NMD), which reduces the...

Action of UPF1 phosphorylation cycle inhibitors. A) A schematic depicting the UPF1 phosphorylation cycle. The mode of action for caffeine and NMDI-1 on this pathway is shown. B) The structure of NMDI-1. The differences between the NMDI-1 and ellipticine structures are indicated. (PDF)

NMDI-1 increases NMD substrate abundance in mouse tissues. IduaW392X mice were administered 5 mg/kg NMDI-1 for 3 days via once daily subcutaneous injections. After treatment, RNA was isolated from the A) brain, B) heart, and C) spleen and analyzed by RT-qPCR to determine the abundance of Idua, Gas5, and Atf4 NMD substrates (normalized to 18S rRNA o...

Scheme for NMDI-1 synthesis. (PDF)

NMDI-1 co-administration with NB84 for 6 days did not further enhance GAG reduction. IduaW392X mice were treated with NB84 for 14 days alone, or supplemented with NMDI-1 during the final 3 days or the final 6 days of NB84 administration. The GAG levels were quantitated in A) brain, B) heart, and C) spleen. The data shown for each column is the aver...

NMDI-1 does not inhibit protein synthesis or suppress PTCs. A) The effect of various NMD inhibitors on total protein synthesis was determined in HeLa cells. 35S-methionine incorporation per microgram of total protein was monitored in untreated cells (−) or cells treated with NMDI-1 (NI1), caffeine (CAF), ellipticine (ELP), or cycloheximide (CHX) as...

NMD attenuators increase the abundance of endogenous NMD substrates in MEFs. RT-qPCR was used to quantify the steady state abundance of endogenous NMD substrates in A) WT and B) IduaW392X MEFs. The data shown are the mean +/− SD (n = 12) of mRNA abundance in treated MEFs relative to untreated MEFs. mRNA abundance was normalized to either 18S rRNA o...

NMDI-1 alone does not reduce GAG accumulation in IduaW392X mice. The micrograms of GAGs per miiligram of defatted, dried tissue were quantitated in A) brain, B) heart, and C) spleen from WT and MPS I-H mice without (−) and with (+) NMDI-1) treatment. The data shown are the mean +/− sd of 6 replicates derived from 3 mice per group (n = 3). p values...

Streptococcus mutans is a major aetiological agent of dental caries. Formation of biofilms is a key virulence factor of S. mutans. Drugs that inhibit S. mutans biofilms may have therapeutic potential. Dihydrofolate reductase (DHFR) plays a critical role in regulating the metabolism of folate. DHFR inhibitors are thus potent drugs and have been expl...

The marine ecosystem presents an immensely rich chemical and biological resource for the discovery of new anticancer drugs. Recently, marine alkaloids, isolated from various aquatic flora and fauna, have been found to exhibit potent anticancer activities. These compounds range structurally from simple linear peptides to complex macrocyclic polyethe...

Kinase inhibitors are among the fastest growing class of anti-cancer therapies. One family of kinases that has recently gained attention as a target for treating malignant disorders is the Tec kinase family. Evidence has been published that one member of this family; the Bmx kinase, may play a role in the pathogenesis of glioblastoma, prostate, bre...

We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results d...

Significant pathways up-regulated by FBA-TPQ. (DOC)

Significant GOs up-regulated by FBA-TPQ. (DOC)