Natural products with therapeutic potential in melanoma metastasis

Malignant melanoma is the most aggressive form of skin cancer and accounts for about 3% of all cases of malignant tumour. Its incidence is increasing worldwide and it is becoming resistant to current therapeutic agents. Natural products continue to provide lead cytotoxic compounds for cancer treatment but less attention has been given to antimigratory compounds. This paper systematically and critically surveys all natural products with direct in vitro and in vivo pharmacological effects on migration and/or metastasis of melanoma cells and maps the mechanisms of action for these underexploited properties. As a result, over 30 natural active principles are described acting mainly through their antagonistic effects upon the TNF-α and EP2 receptors or the suppression of several protein kinases involved in metastatic pathways such as RAS, PI3K, ERK and FAK. Also, some were able to reduce the level of mesenchymal biomarkers such as N-cadherin and/or elevate the expression of other molecules such as E-cadherin. Consequently, downstream transcription factors namely NF-kB, AP-1, ATF-2, CREB, and HIF were inactivated leading to diminished production of MMPs, IL-1, IL-6, COX-2, VEGF and GM-CSF. This review also discusses the opportunity of combination therapies based on natural products and approved drugs, such as the combination of EGCG and dacarbazine, or the combination of two natural compounds such as quercetin and sulforaphane

Differential Anti-Proliferative and Anti-Migratory Activities of Ursolic Acid, 3-O-Acetylursolic Acid and Their Combination Treatments with Quercetin on Melanoma Cells

We evaluate how 3-acetylation modulates the in vitro activity of ursolic acid in melanoma cells alone or in combination treatments with quercetin. Anti-proliferative studies on A375 cells and adult human dermal fibroblasts included analyses on cell cycle distribution, caspase activity, phosphatidylserine translocation, cell morphology and Bax/Bcl-2 protein expression. Then, 2D and 3D migration of B16F10 cells were studied using scratch and Transwell assays, respectively. Ursolic acid and 3-O-acetylursolic acid have shown similar GI50 on A375 cells (26 µM vs. 32 µM, respectively) significantly increased both early and late apoptotic populations, activated caspases 3/7 (48–72 h), and enhanced Bax whilst attenuating Bcl-2 expression. Ursolic acid caused elevation of the sub-G1 population whilst its 3-acetyl derivative arrested cell cycle at S phase and induced strong morphological changes. Combination treatments showed that ursolic acid and quercetin act synergistically in migration assays but not against cell proliferation. In summary, 3-O-acetylursolic acid maintains the potency and overall apoptotic mechanism of the parent molecule with a more aggressive influence on the morphology of A375 melanoma cells but the 3-acetylation suppresses its anti-migratory properties. We also found that ursolic acid can act in synergy with quercetin to reduce cell migration.</jats:p

The in vitro cytotoxicity against human melanoma cells, tyrosinase inhibition and antioxidant activity of Grewia tenax leaves extracts

Grewia tenax (Forssk.) Fiori (Malvaceae) grows in the Arabian Peninsula and is used for several medicinal purposes. To characterize the dermatological bioactivities of G. tenax in terms of its antimelanoma, antityrosinase and antioxidant activities. Cytotoxicity was assessed by cell proliferation and mitochondrial viability assays. Ability to inhibit mushroom tyrosinase and scavenge free radicals were evaluated by an enzymatic and DPPH scavenging microtiter assay, respectively. Phytochemical analyses were carried out using TLC, HPLC-UV and NMR. The chloroform extract shown significant cytotoxic activity in terms of mitochondrial viability (43 ± 14 µg/mL). We identified lupeol and b-sitosterol as the main active components for the tyrosinase inhibitory activity of the hexane extract. Scavenging activity of the DPPH· radical was confined to the water extract. Extracts from this plant have the potential to be used as a base in the development of cosmeceutical products intended to whiten skin or to combat radical-induced physiopathological processes

Muslim pilgrims’ knowledge, attitudes, and practices regarding complementary and alternative medicine (CAM); a study conducted during Hajj season

Complementary and alternative medicine (CAM) has attracted much interest, and its prevalence in both developed and developing countries has increased. During the Hajj season, millions of Muslims from many different countries travel to Makkah for the pilgrimage. In dealing with health issues during the holy season, many pilgrims prefer to self-medicate with traditional remedies instead of visiting medical practitioners, which could affect the efforts of state healthcare organizations to maintain overall public health during this mass gathering. This study aims to gauge the prevalence of CAM use during Hajj, and to assess pilgrims’ beliefs and knowledge of CAM therapies, with particular reference to products available in Makkah. A cross-sectional survey was conducted in several camps and hotels occupied by Hajj pilgrims in Makkah, during Hajj 2023. CAM modalities were used by 68.8 % of the study participants during the Hajj season. There were almost equal numbers of men (53.7 %) and women (46.3 %) participants, with 88 % of the CAM users being non-Saudi and only 12 % Saudi. The majority of the CAM users belonged to two age groups, the 31–40 year group (29.9 %) and the 41–50 year group (34.5 %). The most frequent self-practice therapies were religious prayer/rituals (30.2 %), and the most popular practitioner therapies was herbal treatments (12.3 %). The most common source of CAM-related information was family/friends (29.2 %), for improving well-being reason (25.8 %). More than half of the participants (56.8 %) strongly believed that CAM therapies have the potential to cure disease, although they were unaware of possible interactions between CAM and conventional drugs (76.7 %). More than half of the participants (57.8 %) did not disclose their CAM usage to healthcare practitioners. Half of the sample said they used CAMs during Hajj because of the common belief that therapeutic products from the holy city of Makkah, such as Zamzam water, are more effective. In conclusion, CAM therapies are commonly used by Hajj pilgrims as they are presumed to be natural and therefore safe, raising concerns about the potential risks of relying on CAM without adequate consultation with healthcare providers or awareness of potential interactions between prescription drugs and CAM treatments

In vitro cytotoxic activities of selected Saudi medicinal plants against human malignant melanoma cells (A375) and the isolation of their active principles

Introduction: Natural products are known to be a continuous source of potential anti-cancer agents due to their chemical and biological diversity. This study aimed to evaluate the in vitro cytotoxic properties of medicinal plants and their mechanisms of action in human malignant melanoma cells. Methodology: The study investigated the effect of the cytotoxic extracts on cell cycle, caspase-3/7, apoptosis induction using Annexin V-FITC/PI staining, morphological changes and lactate dehydrogenase activity and 2D cell migration studies. Results: There were 9 extracts considered to be promising (GI50 < 30 µg/mL); Haplophyllum tuberculatum (0.45 µg/mL), Plicosepalus curviflorus (4 µg/mL), Capparis decidua (10 µg/mL), Acacia nilotica (11 µg/mL), Aizoon canariense (14 µg/mL), Carissa edulis (15 µg/mL), Pulicaria schimperi (19 µg/mL) Cyperus rotundus (20 µg/mL), Osteospermum vaillantii (21 µg/mL). Cell cycle arrest at S phase was detected in cells treated with C. decidua, C. edulis, H. tuberculatum, P. curviflorus and P. schimperi. Cellular exposure to A. canariense resulted in G2/M arrest whereas A. nilotica, C. rotundus and O. vaillantii elevated the sub-G1 population. Caspase-3/7 was activated by C. decidua, C. edulis, C. rotundus, H. tuberculatum, P. schimperi and O. vaillantii. Most of the cytotoxic effects were accompanied by externalization of phosphatidylserine and morphological abnormalities like cell shrinkage and chromatin condensation. Lupeol was isolated from C. decidua, justicidin A, B, tuberculatin and tuberculatin acetate from H. tuberculatum and ursolic acid and its acetate from C. edulis as the anti-melanoma principles. Conclusion: The bio-guided isolation of plants extracts led to the identifications of anti-melanoma constituents belonging to different classes including lignans, lignan glycosides, triterpenes and flavonoids

Co-inhibition of p-gp and hsp90 by an isatin-derived compound contributes to the increase of the chemosensitivity of mcf7/adr-resistant cells to doxorubicin

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-κB) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities

Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90&alpha; more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-&#120581;B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90&alpha; genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities