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Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs

Quah SY, Tan MS, Teh YH, Stanslas J

Pharmacol Ther, 2016 06;162:35-57.
PMID: 27016467 DOI: 10.1016/j.pharmthera.2016.03.010

Oncogenic rat sarcoma (Ras) is linked to the most fatal cancers such as those of the pancreas, colon, and lung. Decades of research to discover an efficacious drug that can block oncogenic Ras signaling have yielded disappointing results; thus, Ras was considered "undruggable" until recently. Inhibitors that directly target Ras by binding to previously undiscovered pockets have been recently identified. Some of these molecules are either isolated from natural products or derived from natural compounds. In this review, we described the potential of these compounds and other inhibitors of Ras signaling in drugging Ras. We highlighted the modes of action of these compounds in suppressing signaling pathways activated by oncogenic Ras, such as mitogen-activated protein kinase (MAPK) signaling and the phosphoinositide-3-kinase (PI3K) pathways. The anti-Ras strategy of these compounds can be categorized into four main types: inhibition of Ras-effector interaction, interference of Ras membrane association, prevention of Ras-guanosine triphosphate (GTP) formation, and downregulation of Ras proteins. Another promising strategy that must be validated experimentally is enhancement of the intrinsic Ras-guanosine triphosphatase (GTPase) activity by small chemical entities. Among the inhibitors of Ras signaling that were reported thus far, salirasib and TLN-4601 have been tested for their clinical efficacy. Although both compounds passed phase I trials, they failed in their respective phase II trials. Therefore, new compounds of natural origin with relevant clinical activity against Ras-driven malignancies are urgently needed. Apart from salirasib and TLN-4601, some other compounds with a proven inhibitory effect on Ras signaling include derivatives of salirasib, sulindac, polyamine, andrographolide, lipstatin, levoglucosenone, rasfonin, and quercetin.
Adult community-acquired pneumonia in Malaysia: prediction of mortality from severity assessment on admission

Loh LC, Khoo SK, Quah SY, Visvalingam V, Radhakrishnan A, Vijayasingham P, et al.

Respirology, 2004 Aug;9(3):379-86.
PMID: 15363012

Prediction of mortality in patients with community-acquired pneumonia (CAP) can be assessed using clinical severity scores on admission to hospital. The clinical benefit of such tools is untested in Asian countries. The aim of this study was to determine the early adverse prognostic factors in patients hospitalized with CAP in Malaysia and to assess the usefulness of the British Thoracic Society (BTS) severity criteria.
Addition of macrolide in treating adult hospitalized community-acquired pneumonia

Loh LC, Quah SY, Khoo SK, Vijayasingham P, Thayaparan T

Respirology, 2005 Jun;10(3):371-7.
PMID: 15955152

Current clinical practice guidelines, including those in south Asia, recommend the addition of a macrolide to a broad-spectrum antibiotic for the treatment of severe hospitalized community-acquired pneumonia (CAP). The aim of this study was to observe the influence of macrolide addition on clinical outcomes of hospitalized adult patients with CAP.
Advances and challenges in developing andrographolide and its analogues as cancer therapeutic agents

Soo HL, Quah SY, Sulaiman I, Sagineedu SR, Lim JCW, Stanslas J

Drug Discov Today, 2019 09;24(9):1890-1898.
PMID: 31154065 DOI: 10.1016/j.drudis.2019.05.017

Andrographolide (AGP), a naturally occurring bioactive compound, has been investigated as a lead compound in cancer drug development. Its multidimensional therapeutic effects have raised interest among medicinal chemists, which has led to extensive structural modification of the compound, resulting in analogues with improved pharmacological and pharmaceutical properties. Nevertheless, the analogues with the improved properties need to be rigorously studied to identify drug-like lead compounds. We scrutinised articles published from 2012 to 2018, to objectively provide opinions on the mechanisms of action of AGP and its analogues, as well as their potential as viable anticancer drugs. Preclinical and clinical data, along with the extensive medicinal chemistry efforts, indicate the compounds are potential anticancer agents with specific value in treating recalcitrant cancers such as pancreatic and lung cancers.
Investigation on solution-to-gel characteristic of thermosensitive and mucoadhesive biopolymers for the development of moxifloxacin-loaded sustained release periodontal in situ gels

Sheshala R, Quah SY, Tan GC, Meka VS, Jnanendrappa N, Sahu PS

Drug Deliv Transl Res, 2019 04;9(2):434-443.
PMID: 29392681 DOI: 10.1007/s13346-018-0488-6

The objectives of present research were to develop and characterize thermosensitive and mucoadhesive polymer-based sustained release moxifloxacin in situ gels for the treatment of periodontal diseases. Poloxamer- and chitosan-based in situ gels are in liquid form at room temperature and transform into gel once administered into periodontal pocket due to raise in temperature to 37 °C. Besides solution-to-gel characteristic of polymers, their mucoadhesive nature aids the gel to adhere to mucosa in periodontal pocket for prolonged time and releases the drug in sustained manner. These formulations were prepared using cold method and evaluated for pH, solution-gel temperature, syringeability and viscosity. In vitro drug release studies were conducted using dialysis membrane at 37 °C and 50 rpm. Antimicrobial studies carried out against Aggregatibacter actinomycetemcomitans (A.A.) and Streptococcus mutans (S. Mutans) using agar cup-plate method. The prepared formulations were clear and pH was at 7.01-7.40. The viscosity of formulations was found to be satisfactory. Among the all, formulations comprising of 21% poloxamer 407 and 2% poloxamer 188 (P5) and in combination with 0.5% HPMC (P6) as well as 2% chitosan and 70% β-glycerophosphate (C6) demonstrated an ideal gelation temperature (33-37 °C) and sustained the drug release for 8 h. Formulations P6 and C6 showed promising antimicrobial efficacy with zone of inhibition of 27 mm for A.A. and 55 mm for S. Mutans. The developed sustained release in situ gel formulations could enhance patient's compliance by reducing the dosing frequency and also act as an alternative treatment to curb periodontitis.
Fulltext Over-investigated and under-treated: children with febrile convulsion in a Malaysian district hospital

Lai NM, Tan ML, Quah SY, Tan EL, Foong KW

Singapore Med J, 2010 Sep;51(9):724-9.
PMID: 20938614

We conducted a retrospective audit on the inpatient assessment and care of children admitted with febrile convulsion to Hospital Batu Pahat, a district hospital in Malaysia, using the Malaysian national clinical practice guidelines and the American Academy of Paediatrics practice parameters on febrile convulsion as the reference standards.
Three-year epidemiology of hospitalised paediatric burn patients in a Malaysian Tertiary Hospital 2016 - 2018

Low CX, Kok YQ, Loo XS, Ngim CF, Lim RZM, Quah SY

Med J Malaysia, 2023 Sep;78(5):661-668.
PMID: 37775495

INTRODUCTION: Burn injuries incur not just significant morbidity but also long-term psychosocial impact. This study aims to identify the clinico-demographics of children hospitalised for burns and factors associated with prolonged hospitalisation.
MATERIALS AND METHODS: Written medical records of burn patients admitted to the Sultanah Aminah Hospital paediatric surgical ward, from January 2016 to December 2018, were retrospectively reviewed. Details on the patients' socio-demographic background, burn injuries, management and outcomes were recorded and analysed with logistic regression.
RESULTS AND CONCLUSION: Of the 255 children included in the study, the majority were males (62.7%), children aged between 1 to 3 years (43.1%), and of the Malay ethnic group (83.1%). The commonest injury mechanism was scalds burns (81.2%). Staphylococcus aureus remained the commonest organism cultured from paediatric burn wounds. Most patients (66.4%) were hospitalised for less than 1 week. A significant number of patients experienced complications from their injuries. Multivariate analysis showed burns affecting total body surface area > 10% (adjusted OR, 13.45 [95% CI 6.25 - 28.96]; p = < 0.001) and non-scald burns (adjusted OR, 2.70 [95% CI 1.12 - 6.50]; p = 0.027) were the two main factors associated with prolonged hospitalisation of more than 1 week. These findings describing the epidemiology and outcomes of paediatric burn cases in a tertiary centre in Malaysia may inform future practice. More importantly, the information may contribute to the identification of at-risk populations and advise the development of effective prevention strategies to reduce the incidence and morbidity associated with paediatric burns in this region.
In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

Quah SY, Tan MS, Ho KL, Manan NA, Gorfe AA, Deb PK, et al.

Future Med Chem, 2020 09;12(18):1611-1631.
PMID: 32892640 DOI: 10.4155/fmc-2020-0104

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
Microarray-based identification of differentially expressed genes associated with andrographolide derivatives-induced resistance in colon and prostate cancer cell lines

Quah SY, Wong CC, Wong HC, Ho KL, Abdul Manan N, Deb PK, et al.

Toxicol Appl Pharmacol, 2021 08 15;425:115605.
PMID: 34087331 DOI: 10.1016/j.taap.2021.115605

Chemoresistance poses a major hurdle to cancer treatments. Andrographolide-derived SRJ09 and SRJ23 were reported to exhibit potent, selective inhibitory activities against colon and prostate cancer cells, respectively. In this study, previously developed resistant colon (HCT-116rst09) and prostate (PC-3rst23) cancer cell lines were used to elucidate the molecular mechanisms contributing to chemoresistance. Cytotoxic effects of SRJ09 and SRJ23 on both parental and resistant cells were investigated. Cell cycle distributions in HCT-116rst09 cells following SRJ09 treatment were analysed using flow cytometry. Whole-genome microarray analysis was performed on both parental and resistant cells to obtain differential gene expression profiles. Microarray data were subjected to protein-protein interaction network, functional enrichment, and pathway analyses. Reverse transcription-polymerase chain reaction (RT-PCR) was used to validate the changes in expression levels of selected genes. Besides morphological changes, HCT-116rst09 cells showed 7.0-fold resistance to SRJ09 while PC-3rst23 cells displayed a 5.5-fold resistance to SRJ23, as compared with their respective parental cells. G0/G1-phase cell cycle arrest was observed in HCT-116rst09 cells upon SRJ09 treatment. Collectively, 77 and 21 genes were found differentially modulated in HCT-116rst09 and PC-3rst23 cells, respectively. Subsequent bioinformatics analysis revealed several genes associated with FGFR4 and PI3K pathways, and cancer stemness, were chemoresistance mediators in HCT-116rst09 cells. RT-PCR confirmed the HMOX1 upregulation and ATG12 downregulation protected the PC-3rst23 cells from SRJ23 cytotoxicity. In conclusion, acquired chemoresistance to SRJ09 and SRJ23 in colon and prostate cancer cells, respectively, could be attributed to the alterations in the expression of genes such as those related to PI3K and autophagy pathways.