Papers by Hifzur Siddique
Functionalized graphene oxide loaded GATPT as rationally designed vehicle for cancer-targeted drug delivery
Journal of Drug Delivery Science and Technology, May 1, 2022
Role of epigenetic drugs in sensitizing cancers to anticancer therapies: emerging trends and clinical advancements
Epigenomics, Jun 14, 2023
Epigenetic changes play a significant role in cancer progression, maintenance and therapy resista... more Epigenetic changes play a significant role in cancer progression, maintenance and therapy resistance. Generally, epigenetic modifications are reversible, thereby gaining attention for therapeutic interventions. However, limited efficacy and therapy resistance remain the significant limitations of conventional and epigenetic anticancer therapies. Recently, combination therapies with epigenetic drugs (epi-drugs) and conventional anticancer treatment have gained widespread attention. Here, epi-drugs are administered with anticancer therapies to increase their therapeutic efficacy and sensitize cancer cells resistant to therapies. This review summarizes the mechanism of epi-drugs in reversing resistance to anticancer therapies. Further, the challenges faced during developing combination therapies with epi-drugs are discussed. We believe the clinical benefit of combination therapies could be increased by overcoming the challenges faced during epi-drug development.
Frontiers in Pharmacology, May 2, 2023
Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C 21 H 28 O 2) is an effective phytoster... more Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C 21 H 28 O 2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as antiinflammatory, analgesic, antibacterial, antiseptic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized. Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta-analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool.
Purpose: Metastasis is the major cause of mortality in prostate cancer patients. Factors such as ... more Purpose: Metastasis is the major cause of mortality in prostate cancer patients. Factors such as genetic makeup and race play critical role in the outcome of therapies. This study was conducted to investigate the relevance of BMI1 in metastatic prostate cancer disease in Caucasian and African-Americans. Experimental Design: We employed race-specific prostate cancer models, clinical specimens, clinical data mining, genemicroarray, transcription-reporter assay, chromatin-immunoprecipitation (ChIP), IHC, transgenic-(tgfl/fl) zebrafish, and mouse metastasis models. Results: BMI1 expression was observed to be elevated in metastatic tumors (lymph nodes, lungs, bones, liver) of Caucasian and African-American prostate cancer patients. The comparative analysis of stage III/IV tumors showed an increased BMI1 expression in African-Americans than Caucasians. TCGA and NIH/GEO clinical data corroborated to our findings. We show that BMI1 expression (i) positively correlates to metastatic (MYC, VEGF, cyclin D1) and (ii) negative correlates to tumor suppressor (INKF4A/p16, PTEN) levels in tumors. The correlation was prominent in African-American tumors. We show that BMI1 regulates the transcriptional activation of MYC, VEGF, INKF4A/p16, and PTEN. We show the effect of pharmacological inhibition of BMI1 on the metastatic genome and invasiveness of tumor cells. Next, we show the anti-metastatic efficacy of BMI1-inhibitor in transgenic zebrafish and mouse metastasis models. Docetaxel as monotherapy has poor outcome on the growth of metastatic tumors. BMI1 inhibitor as an adjuvant improved the taxane therapy in race-based in vitro and in vivo models. Conclusions: BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced prostate cancer in patients (including those belonging to high-risk group). Clin Cancer Res; 24(24); 6421-32. Ó2018 AACR.
Supplemental legend from <i>BMI1</i> Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models
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Springer eBooks, Oct 6, 2020
ECM Extracellular matrix rhEGF Recombinant human epidermal growth factor rhPDGF Recombinant human... more ECM Extracellular matrix rhEGF Recombinant human epidermal growth factor rhPDGF Recombinant human platelet-derived growth factor S4PL Syndecan-4 proteo liposomes
Molecular Biology Reports, Jun 29, 2020
Chemotherapy is one of the important treatment modules in early as well as advanced stages of can... more Chemotherapy is one of the important treatment modules in early as well as advanced stages of cancer. However, the major limitation of chemotherapy is the development of chemoresistance in the transformed cells of cancer patients, which leads to cancer recurrence. Long non-coding RNAs (lncRNA) are the transcripts longer than 200 nucleotides in length, which are reported to associate with the initiation, progression, recurrence, and metastasis of different cancers. Several lncRNAs have been implicated in the prevalence of chemoresistant phenotypes and also in the restoration of drug sensitivity in chemoresistant cells. LncRNAs such as HOTAIR, H19, and a lot more are involved in the chemoresistance of cancer cells. Therefore, targeting the lncRNAs may serve as a novel strategy for treating chemoresistant cancer. This review throws light on the role of lncRNA in chemoresistance along with the perspective of the therapeutic targets for the treatment of multiple cancers.
Nature Communications, Jun 17, 2020
Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and... more Tumor-initiating stem-like cells (TICs) are defective in maintaining asymmetric cell division and responsible for tumor recurrence. Cell-fate-determinant molecule NUMB-interacting protein (TBC1D15) is overexpressed and contributes to p53 degradation in TICs. Here we identify TBC1D15-mediated oncogenic mechanisms and tested the tumorigenic roles of TBC1D15 in vivo. We examined hepatocellular carcinoma (HCC) development in alcohol Western diet-fed hepatitis C virus NS5A Tg mice with hepatocyte-specific TBC1D15 deficiency or expression of non-phosphorylatable NUMB mutations. Liver-specific TBC1D15 deficiency or non-p-NUMB expression reduced TIC numbers and HCC development. TBC1D15-NuMA1 association impaired asymmetric division machinery by hijacking NuMA from LGN binding, thereby favoring TIC self-renewal. TBC1D15-NOTCH1 interaction activated and stabilized NOTCH1 which upregulated transcription of NANOG essential for TIC expansion. TBC1D15 activated three novel oncogenic pathways to promote self-renewal, p53 loss, and Nanog transcription in TICs. Thus, this central regulator could serve as a potential therapeutic target for treatment of HCC.
Frontiers in Pharmacology, Jan 11, 2022
Circular RNAs (circRNAs) are the newly uncovered class of non-coding RNAs being cognized as profo... more Circular RNAs (circRNAs) are the newly uncovered class of non-coding RNAs being cognized as profound regulators of gene expression in developmental and disease biology. These are the covalently closed RNAs synthesized when the pre-mRNA transcripts undergo a back-splicing event. In recent years, circRNAs are gaining special attention in the scientific world and are no longer considered as "splicing noise" but rather structurally stable molecules having multiple biological functions including acting as miRNA sponges, protein decoys/scaffolds, and regulators of transcription and translation. Further, emerging evidence suggests that circRNAs are also differentially expressed in multiple cancers where they play oncogenic roles. In addition, circRNAs in association with miRNAs change the expression patterns of multiple transcription factors (TFs), which play important roles in cancer. Thus, the circRNA-miRNA-TFs axis is implicated in the progression or suppression of various cancer types and plays a role in cell proliferation, invasion, and metastasis. In this review article, we provide an outline of the biogenesis, localization, and functions of circRNAs specifically in cancer. Also, we highlight the regulatory function of the circRNA-miRNA-TFs axis in the progression or suppression of cancer and the targeting of this axis as a potential therapeutic approach for cancer management. We anticipate that our review will contribute to expanding the knowledge of the research community about this recent and rapidly growing field of circRNAs for further thorough investigation which will surely help in the management of deadly disease cancer.
Recent Patents on Anti-cancer Drug Discovery, Jan 3, 2020
Background: Cancer is a global health problem and the continuous rise in incidence and mortality ... more Background: Cancer is a global health problem and the continuous rise in incidence and mortality due to cancer carries a real economic burden to all countries. Accumulation of genetic mutation, exposure of environmental carcinogens and food habits due to change in lifestyles are the key reasons for cancer. Targeting cancer cells, we need a multitargeting molecule with low/no toxicity. Objective: To review the current update of the research status of chemopreventive/therapeutic molecule, Apigenin. Methods: Compare the results of the published articles and granted patents on this compound. We also discuss the pros and cons of the present research and future direction. Results: Cancer cells have characteristic alterations and dysregulation of various cell signaling pathways that control cell homeostasis, proliferation, motility, and survival in normal cells. Natural flavonoids are the compounds well known for their anti-inflammatory, anti-oxidant, and anti-cancerous properties. Apigenin, along with several other physiological effects, has a very low intrinsic toxicity and striking effects on the proliferation of cancer cells. Interestingly, this multitargeting molecule is getting wide acceptance among researchers. It is evident from the recent patents filed in this compound. At present, three patents have been granted only on the anticancer properties of apigenin. Conclusion: This mini-review will explain the present research status of apigenin and will further shine some light on how apigenin performs its anti-cancerous actions by interfering with the key cellsignaling pathways.
PLGA-based nanoparticles for the treatment of inflammatory diseases
Elsevier eBooks, 2023
Journal of Biomolecular Structure & Dynamics, Dec 17, 2020
In an attempt to identify suitable nano-carriers for drug delivery, natural drug umbelliferone wa... more In an attempt to identify suitable nano-carriers for drug delivery, natural drug umbelliferone was chosen to synthesize new modulated nanoconjugate of umbelliferone cobalt oxide with cobalt (II) nitrate in one pot assembly in the presence of tannic acid. The synthesized nanoconjugate drug (NCD) was then loaded on graphene oxide (GO) as drug carrier by simple ultrasonication method and thoroughly characterized by various spectroscopic techniques (FT-IR, SEM, TEM, XRD, EPR and thermogravimetric analysis) which revealed the successful loading of the nanoconjugate drug on GO. The UV-visible, fluorescence and electrochemical studies suggested that strong p-p stacking interactions exist between nanoconjugate drug and GO. The binding studies of NCD-GO with ct-DNA were performed by various optical and biophysical methods viz., UV-visible, fluorescence, circular dichroism (CD) and cyclic voltammetry (CV) which indicated electrostatic mode of binding towards the ct-DNA. Furthermore, condensate of nanoconjugate drug-loaded GO (NCD-GO) with ct-DNA was prepared and analyzed by scanning electron microscopy (SEM) which revealed that the interaction of NCD-GO with ct-DNA had occurred. Cleavage activity of NCD-GO with pBR322 was evaluated by gel electrophoresis and it was found that NCD-GO cleave DNA through hydrolytic pathway involving hydroxyl radical (OH). The cytotoxicity of NCD-GO was evaluated against human liver carcinoma (Huh-7), prostate cancer (Du-145) cell lines along with normal cell line (PNT 2). The results obtained showed selective cytotoxic activity of NCD-GO against Du-145 cell lines. The intracellular uptake was visualized by confocal microscopy which revealed the significant cellular uptake and internalization of nanoparticles by cells. Moreover, the adsorption of cobalt oxide umbelliferone on GO was studied by density functional theory. The process of adsorption was found exothermic in nature and the optimized geometry structure is quite stable.
Revisiting inorganic nanoparticles as promising therapeutic agents: A paradigm shift in oncological theranostics
European Journal of Pharmaceutical Sciences, Sep 1, 2021
Cancer remains a global health problem largely due to a lack of effective therapies. Major cancer... more Cancer remains a global health problem largely due to a lack of effective therapies. Major cancer management strategies include chemotherapy, surgical resection, and radiation. Unfortunately, these strategies have a number of limitations, such as non-specific side effects, uneven delivery of the drugs, and lack of proper monitoring technology. Inorganic nanoparticles (NPs) are considered promising agents in treating and tracing cancer due to their unique physicochemical properties such as the controlled release of drugs, bioavailability, biocompatibility, stability, and large surface area. Also, they enhance the solubility of hydrophobic drugs, prolong their circulation time, prevent undesired off-targeting and subsequent side effects, making them efficient particles in cancer theranostics. Promising inorganic-NPs include gold, selenium, silica, and oxide NPs. Further, several techniques are used to modify the surface of inorganic-NPs, making them more efficient for the effective transport of therapeutic cargos to overcome cellular barriers. Thus, inorganic-NPs function effectively, surmounting the intrinsic drawbacks of traditional organic NPs. This mini-review summarizes the significant inorganic-NPs, their properties, surface modifications, cellular uptake, and bio-distributions, along with their potential use in cancer theranostics. We also discuss the promises and challenges faced during the inorganic-NPs mediated therapeutic approach for cancer and these particles' status in the clinical setting.
Apigenin alleviates cancer drug Sorafenib induced multiple toxic effects in Swiss albino mice via anti-oxidative stress
Toxicology and Applied Pharmacology, Jul 1, 2022
Superparamagnetic iron oxide nanoparticles based cancer theranostics: A double edge sword to fight against cancer
Journal of Drug Delivery Science and Technology, Jun 1, 2018
Abstract Cancer is one of the deadliest diseases worldwide and has been responsible for millions ... more Abstract Cancer is one of the deadliest diseases worldwide and has been responsible for millions of deaths. Cancer diagnosis and therapies include various stages such as tumor imaging, cell labeling, drug delivery, gene delivery, hyperthermia, etc. Different regulatory agencies have approved various drugs for the treatment of cancer. However, the efficiency, efficacy, and bioavailability always remain a concern for their effectiveness. Strategies were developed to improve the effectiveness of therapeutic agents and also to minimize their possible side effects. However, their successful application has some drawbacks such as the low efficacy, stability, and biocompatibility. Presently, s uper p aramagnetic i ron o xide n anoparticles (SPIONs) are used in the different field of biomedical research to explore the possible future use in cancer theranostics. Initially, SPIONs showed some limitations; however, later with comprehensive research, the scientist made them stable and more biocompatible through surface modification. The stability and biocompatibility attracted the scientists to use them in different biomedical fields including cancer therapy. Presently, SPIONs are used in both diagnostic and therapeutic purpose to fight against cancer. However, some limitations still exist and warrant further extensive research. In this mini-review, we discuss the different aspects of magnetic nanoparticles especially coated SPIONs for their use in cancer therapy.
Targeting metabolism with herbal therapy: A preventative approach toward cancer
Elsevier eBooks, 2022
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Papers by Hifzur Siddique