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Fulltext Mycomedicine: A Unique Class of Natural Products with Potent Anti-tumour Bioactivities

Dai R, Liu M, Nik Nabil WN, Xi Z, Xu H

Molecules, 2021 Feb 19;26(4).
PMID: 33669877 DOI: 10.3390/molecules26041113

Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.
Repurposing cardiac glycosides for anticancer treatment: a review of clinical studies

Nik Nabil WN, Dai R, Liu M, Xi Z, Xu H

Drug Discov Today, 2024 Aug 03;29(10):104129.
PMID: 39098384 DOI: 10.1016/j.drudis.2024.104129

Cardiac glycosides (CGs), which are traditionally used for heart disease, show promise for cancer therapy. However, there is a lack of a comprehensive review of clinical studies in this area, and so far, CGs have not been widely integrated into clinical cancer treatment. This review covers clinical studies from the past five years, highlighting the potential of CGs to reduce cancer risk, enhance chemotherapy effectiveness, mitigate chemotherapy-induced side effects and improve quality of life. Future clinical trials should personalize the dosage of CGs, integrate molecular testing and investigate immunogenic cell death induction and the potential of CGs for treating bone cancer and metastasis. Optimizing the repurposing of CGs for anticancer treatment requires consideration of specific CGs, cancer types and concurrent medications.
A systematic review on Chinese herbal treatment for radiotherapy-induced xerostomia in head and neck cancer patients

Nik Nabil WN, Lim RJ, Chan SY, Lai NM, Liew AC

Complement Ther Clin Pract, 2018 Feb;30:6-13.
PMID: 29389481 DOI: 10.1016/j.ctcp.2017.10.004

BACKGROUND: Over 80% of head and neck cancer patients suffer from radiotherapy-induced xerostomia (dry mouth). Xerostomia affects cancer patients' quality of life, and xerostomia sometimes persists throughout the patients' lifetime. This review aimed to evaluate the effectiveness and safety of Chinese herbs in relieving radiotherapy induced xerostomia.
METHODS: Systematic searches were conducted on 6 databases (English and Chinese). Studies published up till May 2017 were considered for inclusion.
RESULTS: A final 14 RCTs (total 994 head and neck cancer patients undergoing radiotherapy) compared Chinese herbs with no herbs, were included in analysis. Very low to moderate quality of evidence found Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications (such as oral mucositis and loss of appetite) in head and neck cancer patients.
CONCLUSION: There is limited evidence that Chinese herbal treatment may relief radiotherapy-induced xerostomia and other related complications in head and neck cancer patients.
Fulltext Unveiling the dual role of autophagy in vascular remodelling and its related diseases

Ren H, Dai R, Nik Nabil WN, Xi Z, Wang F, Xu H

Biomed Pharmacother, 2023 Dec;168:115643.
PMID: 37839111 DOI: 10.1016/j.biopha.2023.115643

Vascular remodelling is an adaptive response to physiological and pathological stimuli that leads to structural and functional changes in the vascular intima, media, and adventitia. Pathological vascular remodelling is a hallmark feature of numerous vascular diseases, including atherosclerosis, hypertension, abdominal aortic aneurysm, pulmonary hypertension and preeclampsia. Autophagy is critical in maintaining cellular homeostasis, and its dysregulation has been implicated in the pathogenesis of various diseases, including vascular diseases. However, despite emerging evidence, the role of autophagy and its dual effects on vascular remodelling has garnered limited attention. Autophagy can exert protective and detrimental effects on the vascular intima, media and adventitia, thereby substantially influencing the course of vascular remodelling and its related vascular diseases. Currently, there has not been a review that thoroughly describes the regulation of autophagy in vascular remodelling and its impact on related diseases. Therefore, this review aimed to bridge this gap by focusing on the regulatory roles of autophagy in diseases related to vascular remodelling. This review also summarizes recent advancements in therapeutic agents targeting autophagy to regulate vascular remodelling. Additionally, this review offers an overview of recent breakthroughs in therapeutic agents targeting autophagy to regulate vascular remodelling. A deeper understanding of how autophagy orchestrates vascular remodelling can drive the development of targeted therapies for vascular diseases.
Fulltext Safrana l Prevents Prostate Cancer Recurrence by Blocking the Re-activation of Quiescent Cancer Cells via Downregulation of S-Phase Kinase-Associated Protein 2

Jiang X, Li Y, Feng JL, Nik Nabil WN, Wu R, Lu Y, et al.

Front Cell Dev Biol, 2020;8:598620.
PMID: 33392189 DOI: 10.3389/fcell.2020.598620

The re-proliferation of quiescent cancer cells is considered to be the primary contributor to prostate cancer (Pca) recurrence and progression. In this study, we investigated the inhibitory effect of safranal, a monoterpene aldehyde isolated from Crocus sativus (saffron), on the re-proliferation of quiescent Pca cells in vitro and in vivo. The results showed that safranal efficiently blocked the re-activation of quiescent Pca cells by downregulating the G0/G1 cell cycle regulatory proteins CDK2, CDK4, CDK6, and phospho-Rb at Ser807/811 and elevating the levels of cyclin-dependent kinase inhibitors, p21 and p27. Further investigation on the underlying mechanisms revealed that safranal suppressed the mRNA and protein expression levels of Skp2, possibly through the deregulation of the transcriptional activity of two major transcriptional factors, E2F1 and NF-κB subunits. Moreover, safranal inhibited AKT phosphorylation at Ser473 and deregulated both canonical and non-canonical NF-κB signaling pathways. Safranal suppressed the tumor growth of quiescent Pca cell xenografts in vivo. Furthermore, safranal-treated tumor tissues exhibited a reduction in Skp2, E2F1, NF-κB p65, p-IκBα (Ser32), c-MYC, p-Rb (Ser807), CDK4, CDK6, and CDK2 and an elevation of p27 and p21 protein levels. Therefore, our findings demonstrate that safranal suppresses cell cycle re-entry of quiescent Pca cells in vitro and in vivo plausibly by repressing the transcriptional activity of two major transcriptional activators of Skp2, namely, E2F1 and NF-κB, through the downregulation of AKT phosphorylation and NF-κB signaling pathways, respectively.
Effects of herbal medicine for xerostomia in head and neck cancer patients: an observational study in a tertiary cancer hospital

Lim RJ, Nik Nabil WN, Chan SY, Wong YF, Han LX, Gong JY, et al.

Support Care Cancer, 2019 Sep;27(9):3491-3498.
PMID: 30675667 DOI: 10.1007/s00520-019-4646-2

PURPOSE: More than 80% head and neck cancer patients endured radiotherapy-induced xerostomia which impacts their quality of life (QoL). This observational study evaluated the effect of herbal treatment on head and neck cancer patients' xerostomia and QoL.
METHODS: Head and neck cancer patients were recruited from July 2016 till March 2017 at National Cancer Institute, Ministry of Health, Malaysia. All study participants continued their standard oncology surveillance. Treatment group participants additionally received Chinese herbal treatment. The assessments included unstimulated salivary flow rate (USFR), stimulated salivary flow rate (SSFR), and QoL questionnaire.
RESULTS: Of 42 recruited participants, 28 were in the treatment group and 14 were in the control group. Participants were mainly Chinese (71.4%), stage III cancer (40.5%), and had nasopharynx cancer (76.2%). The commonly used single herbs were Wu Mei, San Qi, and Tian Hua Fen. Sha Shen Mai Dong Tang, Liu Wei Di Huang Wan, and Gan Lu Yin were the frequently prescribed herbal formulas. The baseline characteristics, USFR, SSFR, and QoL between control and treatment groups were comparable (p > 0.05). USFR between control and treatment groups were similar throughout the 6-month study period. SSFR for the treatment group significantly improved from 0.15 ± 0.28 ml/min (baseline) to 0.32 ± 0.22 ml/min (p = 0.04; at the 3rd month) and subsequently achieved 0.46 ± 0.23 ml/min (p = 0.001; at the 6th month). The treatment group had better QoL in terms of speech (p = 0.005), eating (p = 0.02), and head and neck pain (p = 0.04) at the 6th month.
CONCLUSION: Herbal treatment may improve xerostomia and QoL in post-radiotherapy head and cancer patients.
Fulltext Towards a Framework for Better Understanding of Quiescent Cancer Cells

Nik Nabil WN, Xi Z, Song Z, Jin L, Zhang XD, Zhou H, et al.

Cells, 2021 03 05;10(3).
PMID: 33807533 DOI: 10.3390/cells10030562

Quiescent cancer cells (QCCs) are cancer cells that are reversibly suspended in G0 phase with the ability to re-enter the cell cycle and initiate tumor growth, and, ultimately, cancer recurrence and metastasis. QCCs are also therapeutically challenging due to their resistance to most conventional cancer treatments that selectively act on proliferating cells. Considering the significant impact of QCCs on cancer progression and treatment, better understanding of appropriate experimental models, and the evaluation of QCCs are key questions in the field that have direct influence on potential pharmacological interventions. Here, this review focuses on existing and emerging preclinical models and detection methods for QCCs and discusses their respective features and scope for application. By providing a framework for selecting appropriate experimental models and investigative methods, the identification of the key players that regulate the survival and activation of QCCs and the development of more effective QCC-targeting therapeutic agents may mitigate the consequences of QCCs.
Fulltext Saikosaponin A enhances Docetaxel efficacy by selectively inducing death of dormant prostate cancer cells through excessive autophagy

Feng J, Xi Z, Jiang X, Li Y, Nik Nabil WN, Liu M, et al.

Cancer Lett, 2023 Feb 01;554:216011.
PMID: 36442771 DOI: 10.1016/j.canlet.2022.216011

Quiescent cancer cells (QCCs), also known as dormant cancer cells, resist and survive chemo- and radiotherapy, resulting in treatment failure and later cancer recurrence when QCCs resume cell cycle progression. However, drugs selectively targeting QCCs are lacking. Saikosaponin A (SSA) derived from Bupleurum DC., is highly potent in eradicating multidrug-resistant prostate QCCs compared with proliferative prostate cancer cells. By further exacerbating the already increased autophagy through inactivation of Akt-mTOR signaling, SSA triggered cell death in QCCs. Contrarily, inhibition of autophagy or activation of Akt signaling pathway prevented SSA-induced cell death. The multicycle of Docetaxel treatments increased the proportion of QCCs, whereas administering SSA at intervals of Docetaxel treatments aggravated cell death in vitro and led to tumor growth arrest and cell death in vivo. In conclusion, SSA is posed as a novel QCCs-eradicating agent by aggravating autophagy in QCCs. In combination with the current therapy, SSA has potential to improve treatment effectiveness and to prevent cancer recurrence.
Pulsatilla Decoction and its bioactive component β-peltatin induce G2/M cell cycle arrest and apoptosis in pancreatic cancer

Wu R, Xi Z, Liu M, Ren H, Dai R, Jiang X, et al.

Chin Med, 2023 May 28;18(1):61.
PMID: 37246229 DOI: 10.1186/s13020-023-00774-0

BACKGROUND: Pancreatic cancer (PAC), a malignancy that is fatal and commonly diagnosed at a late stage. Despite considerable advancements in cancer treatment, the survival rate of PAC remains largely consistent for the past 60 years. The traditional Chinese medicine formula Pulsatilla Decoction (PD) has been clinically used to treat inflammatory diseases for millennia and recently as a supplementary anti-cancer treatment in China. However, the bioactive ingredients and mechanisms underlying its anti-cancer effect remains unclear.
METHODS: The composition and quality control of PD were verified through analysis by high performance liquid chromatography. Cell viability was determined using Cell Counting Kit-8 assay. The cell cycle distribution was analyzed through PI staining and flow cytometry analysis, while apoptotic cells were measured by double staining with Annexin V-FITC and PI. We used immunoblotting to examine protein expressions. The in vivo effects of β-peltatin and podophyllotoxin were evaluated on a subcutaneously-xenografted BxPC-3 cell nude mice model.
RESULTS: The current study demonstrated that PD markedly inhibited PAC cell proliferation and triggered their apoptosis. Four herbal PD formula was then disassembled into 15 combinations of herbal ingredients and a cytotoxicity assay showed that the Pulsatillae chinensis exerted the predominant anti-PAC effect. Further investigation indicated that β-peltatin was potently cytotoxic with IC50 of ~ 2 nM. β-peltatin initially arrested PAC cells at G2/M phase, followed by apoptosis induction. Animal study confirmed that β-peltatin significantly suppressed the growth of subcutaneously-implanted BxPC-3 cell xenografts. Importantly, compared to podophyllotoxin that is the parental isomer of β-peltatin but clinically obsoleted due to its severe toxicity, β-peltatin exhibited stronger anti-PAC effect and lower toxicity in mice.
CONCLUSIONS: Our results demonstrate that Pulsatillae chinensis and particularly its bioactive ingredient β-peltatin suppress PAC by triggering cell cycle arrest at G2/M phase and apoptosis.