Update and New Insights on Future Cancer Drug Candidates From Plant-Based Alkaloids.

Cancer is a complex multifactorial disease that results from alterations in many physiological and biochemical functions. Over the last few decades, it has become clear that cancer cells can acquire multidrug resistance to conventional anticancer drugs, resulting in tumor relapse. Thus, there is a continuous need to discover new and effective anticancer drugs. Natural products from plants have served as a primary source of cancer drugs and continue to provide new plant-derived anticancer drugs. The present review describes plant-based alkaloids, which have been reported as active or potentially active in cancer treatment within the past 4 years (2017-2020), both in preclinical research and/or in clinical trials. In addition, recent insights into the possible molecular mechanism of action of alkaloid prodrugs naturally present in plants are also highlighted.

Treatment with Lead Chloride During Pregnancy and the Postnatal Period Alters Cell Proliferation and Immune Function in Swiss Albino Mice.

In the current study, we investigated the effect of lead chloride (PbCl2) administration (50 and 100 ppm) on organ and body weight as well as its bioaccumulation during pregnancy and the postnatal period in mice. We showed that lead has no effect on the body weight of mice. However, spleen weight is affected by the two doses of PbCl2 while liver and kidney weights are altered only by the 100-ppm dose. Inductively coupled plasma atomic emission spectrometry (ICP-AES) analysis showed that lead accumulates in the blood, spleen, and thymus. Both doses of PbCl2 significantly reduced splenocyte and thymocyte cell counts after stimulation with lipopolysaccharide (LPS) and phytohemagglutinin A (PHA), respectively. On the other hand, we showed that the levels of Th1 cytokines (interleukin-2 (IL-2), interferon gamma (IFN-γ)), and tumor necrosis factor alpha (TNF-α) were reduced in the serum of mice treated with PbCl2 in a dose-dependent manner, as measured by ELISA. The levels of interleukin-4 (IL-4) and interleukin-10 (IL-10) were very low in untreated mice and were also reduced by treatment with PbCl2. The levels of IL-2, IFN-γ, IL-4, IL-10, and TNF-α secretion differentially decreased in LPS-stimulated splenocytes in lead-treated mice. Using PHA-stimulated thymocytes, we observed a reduction in the levels of IL-2, IL-4, IL-10, and TNF-α in the PbCl2-treated groups. However, IFN-γ concentration in the supernatant of these cells was not decreased when mice were treated with 50 ppm of lead.

Cytotoxicity of new pyridazin-3(2H)-one derivatives orchestrating oxidative stress in human triple-negative breast cancer (MDA-MB-468).

Triple-negative breast cancer (TNBC) is a complex and aggressive subtype of breast cancer characterized by high morbidity and mortality. In the absence of targeted therapy, only chemotherapy is available in this case of cancer. The current study investigated the antitumor effect of new pyridazin-3(2H)-one derivatives on the human TNBC cell line, MD-MB-468. The in vitro cytotoxic activities were investigated using the tetrazolium-based MTT assay. Lipid peroxidation, H2 O2 content, and the specific activities of antioxidant enzymes were also determined. Two molecules, 6f and 7h, were found to be selectively highly active against tumor cells with IC50 values of 3.12 and 4.9 µM, respectively. Furthermore, cells exposed to 6f showed a significant increase in H2 O2 and lipid peroxidation levels, accompanied by a decrease in the enzyme activities of glutathione reductase (GR) and thioredoxin reductase (TrxR). The cytotoxicity of the compound 6f may improve the therapeutic efficacy of the current treatment for TNBC via the inhibition of GR and TrxR activities.

Studies on the Dual Cytotoxicity and Antioxidant Properties of Berberis vulgaris Extracts and Its Main Constituent Berberine.

The present study attempts to investigate the cytotoxic activity of ethanol and ethyl acetate extracts of the Moroccan Berberis vulgaris and its major component berberine, together with exploring their antioxidant properties. It also consists of studying the combination effect of berberine and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, against the human breast adenocarcinoma cell line (MCF-7). Using the MTT assay, we report a differential cytotoxic effect of ethanol and ethyl acetate extracts since the ethanol extract is more cytotoxic than the ethyl acetate one, with IC50 = 3.54 µg/mL and 596.71 µg/mL, respectively. Interestingly, no cytotoxic effect was observed against normal cells. Furthermore, these extracts showed a remarkable antioxidant activity as measured by the DPPH free radicals scavenging assay. In fact, the IC50 values are 69.65 µg/mL and 77.75 µg/mL for the ethanol and ethyl acetate extracts, respectively. In addition, several concentrations of berberine, when combined with the NO donor used at IC30, induced a synergistic cytotoxic activity at concentrations ranging from 8.40 µM to 33.60 µM, as revealed by the combination index values, using the Chou-Talalay method. However, at the other concentrations tested, an antagonistic effect was observed. The observed cytotoxicity was related to apoptosis induction as demonstrated by the annexin-V-streptavidin FITC-staining analysis.

Comparative Phytochemical Analysis of Essential Oils from Different Biological Parts of Artemisia herba alba and Their Cytotoxic Effect on Cancer Cells.

PURPOSE: Carrying out the chemical composition and antiproliferative effects against cancer cells from different biological parts of Artemisia herba alba. METHODS: Essential oils were studied by gas chromatography coupled to mass spectrometry (GC-MS) and their antitumoral activity was tested against P815 mastocytoma and BSR kidney carcinoma cell lines; also, in order to evaluate the effect on normal human cells, oils were tested against peripheral blood mononuclear cells PBMCs. RESULTS: Essential oils from leaves and aerial parts (mixture of capitulum and leaves) were mainly composed by oxygenated sesquiterpenes 39.89% and 46.15% respectively; capitulum oil contained essentially monoterpenes (22.86%) and monocyclic monoterpenes (21.48%); esters constituted the major fraction (62.8%) of stem oil. Essential oils of different biological parts studied demonstrated a differential antiproliferative activity against P815 and BSR cancer cells; P815 cells are the most sensitive to the cytotoxic effect. Leaves and capitulum essential oils are more active than aerial parts. Interestingly, no cytotoxic effect of these essential oils was observed on peripheral blood mononuclear cells. CONCLUSION: Our results showed that the chemical composition variability of essential oils depends on the nature of botanical parts of Artemisia herba alba. Furthermore, we have demonstrated that the differential cytotoxic effect depends not only on the essential oils concentration, but also on the target cells and the botanical parts of essential oils used.