Synthesis and Characterization of the Ethylene-Carbonate-Linked L-Valine Derivatives of 4,4-Dimethylcurcumin with Potential Anticancer Activities

Natural phenolic products from herbal medicines and dietary plants constitute the main source of lead compounds for the development of the new drug. 4,4-Dimethylcurcumin (DMCU) is a synthetic curcumin derivative and exhibits anticancer activities against breast, colon, lung, and liver cancers. However, further development of DMCU is limited by unfavorable compound properties such as very low aqueous solubility and moderate stability. To increase its solubility, we installed either or both of the ethylene-carbonate-linked L-valine side chains to DMCU phenolic groups and produced targeted 1-trifluoroacetic acid (1-TFA) and 2-trifluoroacetic acid (2-TFA) derivatives. The terminus L-valine of ethylene-carbonate-linked side chain is known to be a L-type amino acid transporter 1 (LAT1) recognition element and therefore, these two derivatives were expected to readily enter into LAT1-expressing cancer cells. In practice, 1-TFA or 2-TFA were synthesized from DMCU in four steps with 34–48% overall yield. Based on the corresponding LC-MS analysis, water solubility of DMCU, 1-TFA, and 2-TFA at room temperature (25 ± 1 °C) were 0.018, 249.7, and 375.8 mg/mL, respectively, indicating >10,000-fold higher solubility of 1-TFA and 2-TFA than DMCU. Importantly, anti-proliferative assay demonstrated that 2-TFA is a potent anti-cancer agent against LAT1-expressing lung cancer cells NCI-H460, NCI-H358, and A549 cells due to its high intracellular uptake compared to DMCU and 1-TFA. In this study, we logically designed and synthesized the targeted compounds, established the LC-MS analytical methods for evaluations of drug solubility and intracellular uptake levels, and showed improved solubility and anti-cancer activities of 2-TFA. Our results provide a strategical direction for the future development of curcuminoid-like phenolic compounds.

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Natural-Derived Molecules as a Potential Adjuvant in Chemotherapy: Normal Cell Protectors and Cancer Cell Sensitizers

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666210623104227 ◽

2021 ◽

Vol 21 ◽

Author(s):

Rajib Hossain ◽

Muhammad Torequl Islam ◽

Mohammad S. Mubarak ◽

Divya Jain ◽

Rasel Khan ◽

...

Keyword(s):

Oxidative Stress ◽

Side Effects ◽

Cancer Cells ◽

Chemotherapeutic Agents ◽

Polyphenolic Compounds ◽

Anticancer Effect ◽

Anticancer Activities ◽

Normal Cells ◽

Anti Cancer ◽

Global Threat

Background: Cancer is a global threat to humans and a leading cause of death worldwide. Cancer treatment includes, among other things, the use of chemotherapeutic agents, compounds that are vital for treating and preventing cancer. However, chemotherapeutic agents produce oxidative stress along with other side effects that would affect the human body. Objective: To reduce the oxidative stress of chemotherapeutic agents in cancer and normal cells by naturally derived compounds with anti-cancer properties, and protect normal cells from the oxidation process. Therefore, the need to develop more potent chemotherapeutics with fewer side effects has become increasingly important. Method: Recent literature dealing with the antioxidant and anticancer activities of the naturally naturally-derived compounds: morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin has been surveyed and examined in this review. For this, data were gathered from different search engines, including Google Scholar, ScienceDirect, PubMed, Scopus, Web of Science, Scopus, and Scifinder, among others. Additionally, several patient offices such as WIPO, CIPO, and USPTO were consulted to obtain published articles related to these compounds. Result: Numerous plants contain flavonoids and polyphenolic compounds such as morin, myricetin, malvidin, naringin, eriodictyol, isovitexin, daidzein, naringenin, chrysin, and fisetin, which exhibit ‎antioxidant, anti-inflammatory, and anti-carcinogenic actions via several mechanisms. These compounds show sensitizers of cancer cells and protectors of healthy cells. Moreover, these compounds can reduce oxidative stress, which is accelerated by chemotherapeutics and exhibit a potent anticancer effect on cancer cells. Conclusions: Based on these findings, more research is recommended to explore and evaluate such flavonoids and polyphenolic compounds.

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Synthesis, Antibacterial and Anticancer Activities Evaluation of New 4-Thiazolidinone-Indolin-2-One Analogs

Biointerface Research in Applied Chemistry ◽

10.33263/briac126.80948104 ◽

2021 ◽

Vol 12 (6) ◽

pp. 8094-8104

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

A549 Cells ◽

Cancer Cell Line ◽

Mitochondrial Pathway ◽

Knoevenagel Reaction ◽

Anticancer Activities ◽

Dapi Staining ◽

Mcf 7

A series of novel thiazolidinone-isatin hybrids have been synthesized through the Knoevenagel reaction of isatin derivatives with synthesized thiazolidinone scaffolds and then evaluated for their in vitro antibacterial effects on Escherichia coli (E.coli) and Staphylococcus aureus (S.aureus). Cytotoxic effects of the compounds on non-small-cell lung cancer cells (A549 cells), breast epithelial cancer cell line (MCF-7), and prostate cancer cells (PC3 cells) were investigated. Among compounds tested for antibacterial activity, S. aureus was susceptible to compound 7d. The most potent compounds against A549, MCF-7, and PC3 tumor cells were found to be 7g. DAPI staining of all cancer cell lines treated with compound 7g, associated with cell death. We finally confirmed that apoptosis occurred in A549 cells by up-regulated Bax expression and down-regulated Bcl-2 expression from the mitochondrial pathway of apoptosis by using the quantitative reverse transcription-polymerase chain reaction (qRT-PCR) method. Our findings suggested that compound 7g may be a good target in designing cancer therapy strategies.

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Herbal Medicines Attenuate PD-L1 Expression to Induce Anti-Proliferation in Obesity-Related Cancers

Nutrients ◽

10.3390/nu11122979 ◽

2019 ◽

Vol 11 (12) ◽

pp. 2979 ◽

Cited By ~ 4

Author(s):

Yu-Chen S.H. Yang ◽

Zi-Lin Li ◽

Ya-Jung Shih ◽

James A. Bennett ◽

Jaqueline Whang-Peng ◽

...

Keyword(s):

Cancer Cells ◽

Herbal Medicines ◽

Cancer Proliferation ◽

Programmed Death ◽

New Findings ◽

Tnf Α ◽

Anti Cancer ◽

Obesity And Cancer ◽

Cell Death Protein ◽

Necrosis Factor

Pro-inflammatory hormones and cytokines (leptin, tumor necrosis factor (TNF)-α, and interleukin (IL)-6) rise in obesity. Elevated levels of hormones and cytokines are linked with several comorbidities such as diabetes, heart disease, and cancer. The checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) plays an important role in obesity and cancer proliferation. L-thyroxine (T4) and steroid hormones up-regulate PD-L1 accumulation and promote inflammation in cancer cells and diabetics. On the other hand, resveratrol and other herbal medicines suppress PD-L1 accumulation and reduce diabetic effects. In addition, they induce anti-cancer proliferation in various types of cancer cells via different mechanisms. In the current review, we discuss new findings and visions into the antagonizing effects of hormones on herbal medicine-induced anti-cancer properties.

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ER–Mitochondria Calcium Flux by β-Sitosterol Promotes Cell Death in Ovarian Cancer

Antioxidants ◽

10.3390/antiox10101583 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1583

Author(s):

Hyocheol Bae ◽

Sunwoo Park ◽

Jiyeon Ham ◽

Jisoo Song ◽

Taeyeon Hong ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Calcium Influx ◽

Cell Aggregation ◽

Calcium Flux ◽

Ovarian Cancer Cells ◽

Human Ovarian Cancer ◽

Anticancer Activities ◽

Anticancer Effects ◽

Anti Cancer

Phytosterols, which are derived from plants, have various beneficial physiological effects, including anti-hypercholesterolemic, anti-inflammatory, and antifungal activities. The anticancer activities of natural products have attracted great attention, being associated with a low risk of side effects and not inducing antineoplastic resistance. β-sitosterol, a phytosterol, has been reported to have anticancer effects against fibrosarcoma and colon, breast, lung, and prostate cancer. However, there are no reports of its activity against ovarian cancer. Therefore, we investigated whether β-sitosterol shows anticancer effects against ovarian cancer using human ovarian cancer cell lines. We confirmed that β-sitosterol induced the apoptosis of ovarian cancer cells and suppressed their proliferation. It triggered pro-apoptosis signals and the loss of mitochondrial membrane potential, enhanced the generation of reactive oxygen species and calcium influx through the endoplasmic reticulum–mitochondria axis, and altered signaling pathways in human ovarian cancer cells. In addition, we observed inhibition of cell aggregation, suppression of cell growth, and decreased cell migration in ovarian cancer cells treated with β-sitosterol. Further, our data obtained using ovarian cancer cells showed that, in combination with standard anti-cancer drugs, β-sitosterol demonstrated synergistic anti-cancer effects. Thus, our study suggests that β-sitosterol may exert anti-cancer effects against ovarian cancer in humans.

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Discovering and Characterizing of Survivin Dominant Negative Mutants With Stronger Pro-apoptotic Activity on Cancer Cells and CSCs

Frontiers in Oncology ◽

10.3389/fonc.2021.635233 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Guo ◽

Xingyuan Ma ◽

Yunhui Fu ◽

Chang Liu ◽

Qiuli Liu ◽

...

Keyword(s):

Stem Cells ◽

Cancer Cells ◽

A549 Cells ◽

Dominant Negative ◽

Dominant Negative Mutant ◽

Anti Cancer ◽

Apoptotic Activity ◽

Reversal Index ◽

Negative Mutant

Survivin as a member of the inhibitor of apoptosis proteins (IAPs) family is undetectable in normal cells, but highly expressed in cancer cells and cancer stem cells (CSCs) which makes it an attractive target in cancer therapy. Survivin dominant negative mutants have been reported as competitive inhibitors of endogenous survivin protein in cancer cells. However, there is a lack of systematic comparative studies on which mutants have stronger effect on promoting apoptosis in cancer cells, which will hinder the development of novel anti-cancer drugs. Here, based on the previous study of survivin and its analysis of the relationship between structure and function, we designed and constructed a series of different amino acid mutants from survivin (TmSm34, TmSm48, TmSm84, TmSm34/48, TmSm34/84, and TmSm34/48/84) fused cell-permeable peptide TATm at the N-terminus, and a dominant negative mutant TmSm34/84 with stronger pro-apoptotic activity was selected and evaluated systematically in vitro. The double-site mutant of survivin (TmSm34/84) showed more robust pro-apoptotic activity against A549 cells than others, and could reverse the resistance of A549 CSCs to adriamycin (ADM) (reversal index up to 7.01) by decreasing the expression levels of survivin, P-gp, and Bcl-2 while increasing cleaved caspase-3 in CSCs. This study indicated the selected survivin dominant negative mutant TmSm34/84 is promising to be an excellent candidate for recombinant anti-cancer protein by promoting apoptosis of cancer cells and their stem cells and sensitizing chemotherapeutic drugs.

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Repurposing Itraconazole Loaded PLGA Nanoparticles for Improved Antitumor Efficacy in Non-Small Cell Lung Cancers

Pharmaceutics ◽

10.3390/pharmaceutics11120685 ◽

2019 ◽

Vol 11 (12) ◽

pp. 685 ◽

Cited By ~ 10

Author(s):

Nabil A. Alhakamy ◽

Shadab Md

Keyword(s):

Cancer Cells ◽

Therapeutic Agent ◽

Water Solubility ◽

Molecular Level ◽

Controlled Drug Release ◽

Plga Nanoparticles ◽

Anticancer Activities ◽

Drug Release Profile ◽

Lung Cancers ◽

Bcl2 Protein

Itraconazole (ITR) is a broad-spectrum antifungal drug, which has been shown to possess some promising anticancer, anti-proliferative, and anti-angiogenic properties in some cancers, such as cancers of the lung, breast, and skin. However, ITR has some drawbacks, such as poor water solubility, which hinder its use as a therapeutic agent. Therefore, in the present study, we developed and characterized chitosan-coated PLGA nanoparticles of itraconazole and studied their anticancer activities in H1299 lung cancer cells. The prepared ITR nanoparticles showed a small particle size, narrow poly dispersity index (PDI), positive zeta potential, and a controlled drug release profile. The cytotoxicity of ITR nanoparticles (NPs) on H1299 cancer cells after 24 h of exposure was greater than that of the ITR solution. Apoptosis of cancer cells exposed to ITR nanoparticles was also enhanced in comparison with the ITR solution. At the molecular level, ITR NPs were more effective than ITR solution in inducing pro-apoptotic Bax and p53 while reducing anti-apoptotic Bcl2 protein expression. ITR NPs were more effective than ITR solution in arresting cells both at the G0/G1 as well as G2/M phases of the cell cycle. Hence, repurposing itraconazole by encapsulation into PLGA NPs with chitosan coating is a potentially promising approach to treat lung cancers.

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Chemical composition and anticancer activities of methanol-extracted agarwood (Gyrinops verstegii [Gilg.] Domke)

IOP Conference Series Earth and Environmental Science ◽

10.1088/1755-1315/914/1/012070 ◽

2021 ◽

Vol 914 (1) ◽

pp. 012070

Author(s):

T K Waluyo ◽

G Pasaribu ◽

I Winarni

Keyword(s):

Chemical Composition ◽

Cancer Cells ◽

Type A ◽

Anticancer Activities ◽

Methanol Extraction ◽

Mtt Method ◽

Anti Cancer

Abstract This research aimed to study about chemical composition and anti-cancer activities of natural agarwood and cultivated agarwood (Gyrinops vertegii [Gilg.] Domke). Agarwood used in the research was of lowest qualities, which comprised agarwood with natural kemedangan type (A), with cultivated kemedangan-I type (B1), and with cultivated kemedangan-II type (B2), all after methanol extraction. Chemical composition was examined using GC-MS instrument, meanwhile tests on lungs associated anticancer activities (A549’s cancer cells) were performed using MTT method. Chemical composition in low-quality agarwoods was predominantly sesquiterpene compounds, comprising among others guaiacol, cumene, aromadendrene, aplha-humulene, velleral, etc; and conservely did not contain chromone derivative compounds which are compounds characterizing quality agarwood. Low-quality agarwood extracts afforded efficacious potency as anticancer actions against A549’s lungs-attacking cancer cells with IC50 values at 144.92 µgmL−1 (A); IC50 at 206.88 µgmL−1 (B1), and IC50 187.97 µgmL−1 (B2).

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Application of Nanoemulsion in Cancer Treatment

10.4018/978-1-7998-8378-4.ch011 ◽

2022 ◽

pp. 237-258

Author(s):

Sumira Malik ◽

Shristi Kishore ◽

Manisha Kumari ◽

Archna Dhasmana

Keyword(s):

Multidrug Resistance ◽

Cancer Treatment ◽

Cancer Cells ◽

Water Solubility ◽

Cancer Therapeutics ◽

Current Status ◽

Valuable Contribution ◽

Therapeutic Application ◽

Commercial Importance ◽

Anti Cancer

Nanoemulsions are pharmaceutical-based nanometres ranged nanoformulated particles with significant and valuable contribution in field of the nanotechnology. In cancer treatment, the treatment through drugs fails primarily due to multidrug resistance (MDR), poor solubility, and unspecific toxicity. Nanoemulsions have the remarkable properties of non-immunogenicity, biodegradability, sustained encapsulation of low water solubility drugs, sustained regulated release of drug, stable and safe carrying tendency to deliver such drugs, and specificity in targeting only cancer cells to overcome multidrug resistance through for clinical and therapeutic application. They excellently address the noncompliance issues associated with the conventional anti-cancerous chemotherapeutic dosage issues. Currently multifunctional nanoemulsions are under experimentation for the treatment of various types of cancer. The chapter highlights the current status and applications of nanoemulsions as anti-cancer therapeutics and their commercial importance.

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AKT/GSK-3 Pathway targeting; Botanicals and Bioactive Compounds with Anticancer Activities

Current Pharmaceutical Design ◽

10.2174/1381612827666210118122909 ◽

2021 ◽

Vol 27 ◽

Author(s):

Atefeh Jalali ◽

Mohammad M. Zarshenas

Keyword(s):

Natural Products ◽

Cancer Cells ◽

Signaling Pathways ◽

Signaling Pathway ◽

Cancer Progression ◽

Herbal Medicines ◽

Signal Pathways ◽

Anticancer Activities ◽

Critical Signal ◽

Late 20Th Century

Background: In the late 20th century, the leading role of signaling pathways in various cancers is revealed via some genome's systematic investigations. The Akt/GSK-3 signaling pathway is one of the critical signaling pathways dysregulated in numerous human cancers. The Akt cascade acts in the cancer process by regulating apoptosis, cell cycle, metabolism, and cells' longevity. The GSK-3 is downstream of Akt has an opposite role in cancer progression. Objective: Attending to the importance of the Akt/GSK-3 pathway in cancer progression and the positive result of natural products in cancer treatment, this research is designed to review effective herbal medicines in one of the involvement critical signal pathways of cancer for developing novel anticancer drugs. Method: Keywords "plant", "natural", "cancer", "AKT", and "GSK" were searched through the "Scopus" and "Google scholar" databases up to 30th August 2020. Papers linking to pharmacology, toxicology, and pharmaceutics were collected and discussed. Results and conclusion: The Akt/GSK-3 signaling pathway plays a prominent role in cancer. Although the effect of GSK-3 in cancer cells is depended on the type and contents of cells, the inhibition of Akt/GSK-3 mostly is led to three primary outcomes in cancer cells, including (1) apoptotic activity and autophagy induction, (2) anti-proliferative and growth inhibitory effects, and (3) anti-metastatic and angiogenesis effects. As the tendency to use natural products increases, we gathered 64 plants or bioactive components with the anticancer activity via the Akt/GSK-3 signaling pathway. Since most of these investigations have been done on cell lines, these plants can be the right candidate to be evaluated in human trials.

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Apoptotic Cell Death Induction Through Pectin, Guar Gum and Zinc Oxide Nanocomposite in A549 Lung Adenocarcinomas

Biointerface Research in Applied Chemistry ◽

10.33263/briac122.18561869 ◽

2021 ◽

Vol 12 (2) ◽

pp. 1856-1869

Keyword(s):

Cell Death ◽

Zinc Oxide ◽

Cancer Cells ◽

Guar Gum ◽

Apoptotic Cell ◽

Human Peripheral Blood ◽

Reactive Oxygen Species Generation ◽

A549 Cells ◽

Target Cells ◽

Anti Cancer

Previously, we reported the immunostimulatory potential of the nanocomposite prepared from biopolymers (Pectin and Guar gum) and zinc oxide (Pec-gg-ZnO) on human peripheral-blood lymphocytes leading to enhanced anti-cancer immunity. The current study aims to describe the direct anti-cancer potential of Pec-gg-ZnO nanocomposite and the relevant mechanism of cell death induction in human lung carcinomas (A549). The cytotoxicity assay revealed the anti-cancer potential of Pec-gg-ZnO nanocomposite towards A549 cells, cervical adenocarcinoma (HeLa), and prostatic small cell carcinoma (PC-3). The IC50 values were 83.67 ± 0.10 μg/ml, 87.25 ± 0.03 μg/ml and 85.95 ± 0.03 μg/ml for A549, HeLa and PC-3 cells, respectively. The nanocomposite's cancer cells' killing capabilities were significantly higher than pectin and guar gum alone. Hemolysis assay revealed that synthesized Pec-gg-ZnO nanocomposite is biocompatible at 2.5 mg/ml. S phase arrest with enhanced sub-G1 (apoptotic cells) population was examined in A549 cells treated with Pec-gg-ZnO nanocomposite. The nanocomposite caused apoptosis of target cells by inducing mitochondrial depolarisation, reactive oxygen species generation, caspase-3 and Poly (ADP-ribose) polymerase 1 (PARP1) activation resulting in DNA fragmentation. Collectively, the current data revealed that Pec-gg-ZnO nanocomposite is a novel polymer-based anti-cancer agent capable of inducing apoptotic pathways in cancer cells.

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