Epigallocatechin Gallate Derivative Y6 Reverses Oxaliplatin Resistance in Hepatocellular Carcinoma via Targeting the MiR-338-3p/HIF-1α/TWIST Axis to Inhibit EMT.

BACKGROUND: The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC. METHODS: MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drugresistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/Twist proteins, and EMT-related proteins. RESULTS: We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and Twist was down-regulated. CONCLUSION: Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

Combinatorial therapeutic enzymes to combat multidrug resistance in bacteria.

AIMS: Antibiotic resistance including multidrug resistance (MDR) is a negative symbol to the human health system because it loses the capability to treat infections. Unfortunately, the available antibiotics do not show an effective therapeutic response against bacterial infections. In the situation of global antibiotic unresponsiveness, enzymatic therapy especially in combinatorial form seems an effective approach to control bacterial infection and combat resistance. The article is important because it focuses on combinatorial enzymatic therapy that has multiple properties (effective antibacterial performances, antibiofilm capacity, immunomodulators, targeted actions, synergistic actions, multiple targeting, and resistance-proof properties) and can address antibiotic resistance effectively. MATERIALS AND METHODS: We searched the related topics with Pubmed, Scopus, and Google Scholar databases and finally 73 relevant papers were reviewed in detail and cited in this article. KEY FINDINGS: Discusses properties of combinatorial therapeutic enzymes made it an accomplished means over antibiotic therapy. This article discusses the need for combinatorial enzymatic therapy against bacterial infection, its distinguished features, and properties with multi-mechanistic antibacterial action. It discussed the European Medicine Agency and Food and Drug Administration-approved therapeutic enzymes (antibacterial and antibiofilm). SIGNIFICANCE: This article provided the possible combination of the enzyme that may be used as an antibacterial agent along with limitations and future scope of combinatorial antibacterial enzymatic agents. This article could draw the attention of researchers to combinatorial therapeutic enzymatic molecules as effective and futuristic therapy to overcome the problem of multiple antibiotic resistance in bacteria.

Sesquiterpene dimers with a rare skeleton from Chloranthus holostegius exhibiting multidrug resistance reversal activity in vitro and in vivo.

Two previously unreported lindenane sesquiterpene dimers (1 and 2) with a rare skeleton containing an oxaspiro[4.5]decane moiety were isolated from the roots of Chloranthus holostegius var. trichoneurus. Their structures were elucidated by HRESIMS, NMR, ECD, and NMR quantum chemical calculations, along with DP4+ probability analysis. In bioassay, compound 1 exhibited significant activity to reverse the multidrug resistance (MDR)in MCF-7/ADR cells, with an IC50 value of 4.4 µM. Further mechanistic studies revealed that compound 1 combined with doxorubicin could induce apoptosis of MCF-7/ADR cells and block the cell cycle in the G2/M phase. Mechanistically, compound 1 could inhibit the efflux function of P-glycoprotein (P-gp) using the zebrafish model. Finally, the enhanced chemotherapeutic effects of doxorubicin were further confirmed by in vivo zebrafish xenograft experiments.

Novel pyxinol amide derivatives bearing an aliphatic heterocycle as P-glycoprotein modulators for overcoming multidrug resistance.

P-glycoprotein (Pgp) modulators are promising agents for overcoming multidrug resistance (MDR) in cancer chemotherapy. In this study, via structural optimization of our lead compound S54 (nonsubstrate allosteric inhibitor of Pgp), 29 novel pyxinol amide derivatives bearing an aliphatic heterocycle were designed, synthesized, and screened for MDR reversal activity in KBV cells. Unlike S54, these active derivatives were shown to transport substrates of Pgp. The most potent derivative 4c exhibited promising MDR reversal activity (IC50 of paclitaxel = 8.80 ± 0.56 nM, reversal fold = 211.8), which was slightly better than that of third-generation Pgp modulator tariquidar (IC50 of paclitaxel = 9.02 ± 0.35 nM, reversal fold = 206.6). Moreover, the cytotoxicity of this derivative was 8-fold lower than that of tariquidar in human normal HK-2 cells. Furthermore, 4c blocked the efflux function of Pgp and displayed high selectivity for Pgp but had no effect on its expression and distribution. Molecular docking revealed that 4c bound preferentially to the drug-binding domain of Pgp. Overall, 4c is a promising lead compound for developing Pgp modulators.

Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 µM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 µM, respectively.

Articulate Chemotherapeutic Strategies for the Development of Effective Drugs against a Fatal Disease, Visceral Leishmaniasis.

Visceral Leishmaniasis (VL) control relies mainly on chemotherapy in the absence of no effective vaccines. However, available anti-VL drugs are limited in number, having toxicity issues, adverse reactions, low efficacy, and resistance observed against antileishmanial. A significant decrease in efficacy (~tenfold increase in dosage and duration) was reported against the usual treatment with Pentavalent antimonials (the most recommended antileishmanial drug discovered 90 years ago). Amphotericin B is the second line of treatment but limits wider use due to its high cost. Pentamidine is another anti-VL drug, but its therapeutic efficacy has decreased significantly in different areas. These conventional therapeutics for VL have become almost outdated due to a significant increase in therapeutic failure in terms of percentage. Due to this, the search for an effective future anti-VL drug spans several decades, and now it is in high demand in the current situation. Some conventional therapeutics are modified, but they are also not satisfactory. Therefore, this article aimed to discuss conventional and modified therapeutics while emphasizing innovative chemotherapeutic measures against VL that could speed up the slow pace of antileishmanial drugs and overcome the drug resistance problem in the future.

Antimicrobial and Adjuvant Potencies of Di-n-alkyl Substituted Diazalariat Ethers.

Lariat ethers are macrocyclic polyethers-crown ethers-to which sidearms are appended. 4,13-Diaza-18-crown-6 having twin alkyl chains at the nitrogens show biological activity. They exhibit antibiotic activity, but when co-administered at with an FDA-approved antibiotic, the latter's potency is often strongly enhanced. Potency enhancements and resistance reversals have been documented in vitro for a range of Gram-negative and Gram-positive bacteria with a variety of antimicrobials. Strains of E. coli and Staphylococcus aureus having resistance to a range of drugs have been studied and the potency enhancements (checkerboards) are reported here. Drugs included in the present study are ampicillin, cefepime, chlortetracycline, ciprofloxacin, doxycycline, kanamycin, minocycline, norfloxacin, oxycycline, penicillin G, and tetracycline. Enhancements of norfloxacin potency against S. aureus 1199B of up to 128-fold were observed. The properties of these lariat ethers have been studied to determine solubility, their membrane penetration, cytotoxicity and mammalian cell survival, and their effect on bacterial efflux pumps. It is shown that in some cases, the lariat ethers have complex antimicrobials with considerable selectivity. Based on these observations, including 1:1 complexation between lariat ethers and antimicrobials and the cytotoxicity of the MeI salts showing a separation index of 32-fold, they hold significant potential for further development.

Photopolymerized keratin-PGLa hydrogels for antibiotic resistance reversal and enhancement of infectious wound healing.

Infectious wounds have become serious challenges for both treatment and management in clinical practice, so development of new antibiotics has been considered an increasingly difficult task. Here, we report the design and synthesis of keratin 31 (K31)-peptide glycine-leucine-amide (PGLa) photopolymerized hydrogels to rescue the antibiotic activity of antibiotics for infectious wound healing promotion. K31-PGLa displayed an outstanding synergistic effect with commercial antibiotics against drug-resistant bacteria by down-regulating the synthesis genes of efflux pump. Furthermore, the photopolymerized K31-PGLa/PEGDA hydrogels effectively suppressed drug-resistant bacteria growth and enhanced skin wound closure in murine. This study provided a promising alternative strategy for infectious wound treatment.

Can the use of larviciding with biological compounds contribute in increasing Anopheles gambiae s.l. susceptibility to pyrethroid in a population expressing high resistance intensity?

BACKGROUND: Larviciding using non-insecticide compounds is considered appropriate for controlling outdoor biting mosquitoes and for managing insecticide resistance. However, there is still not enough information on the influence of larviciding in managing pyrethroid resistance. In the present study, we checked whether the introduction of larviciding using the biolarvicide VectoMax G in the city of Yaoundé is contributing in restoring the susceptibility of An. coluzzii populations to pyrethroids. METHODOLOGY: The susceptibility status of field An. coluzzii population was evaluated at different time points before and during larviciding treatments. In addition, An. coluzzii larvae collected in the city of Yaoundé, were split into four groups and exposed to different selection regimes for many generations as follow; (i): deltamethrin 0.05%_only, (ii): Vectomax_only, (iii): Vectomax+deltamethrin 0.05%, (iv): VectoMax+deltamethrin 0.05% + susceptible. Life traits parameters were measured in the progeny and compared between colonies. The control was the susceptible laboratory strain "Ngousso". Kdr allele frequency and the profile of expression of different detoxification genes and oxidative stress genes was checked using qPCR analysis. Gene's expression was compared between the first and the last generation of each colony and in field populations collected before and during larviciding. RESULTS: An increase in mosquito susceptibility to deltamethrin and permethrin was recorded for the field populations after larviciding implementation. Resistance intensity to deltamethrin was found to decrease from high to low in field populations. Only the colony vectomax+deltamethrin+susceptible presented a high susceptibility to deltamethrin after 21 generations. The kdr gene frequency was found to be unchanged in the field population and laboratory colonies. A significant decrease in the overexpression profile of Gste2 was detected in field population after larviciding implementation. Other genes showing a similar pattern though not significant were Cyp6z1, Cyp6p1 and Cyp6g16. Concerning fitness only the colony vectomax+deltamethrin+susceptible was found to display a fitness profile similar to the susceptible colony with high fecundity, high hatching rate, short development time and long adult survival rate. CONCLUSION: The profile of the field population supported reversal of phenotypic resistance to pyrethroids however no reduction in the frequency of the kdr allele was recorded. Some detoxification genes were detected less overexpressed. The study suggest that reversal may take longer to achieve in a population expressing a very high resistance profile and under continuous insecticide selection pressure.

Cycloartane-type triterpenoids and steroids from Trichilia connaroides and their multidrug resistance reversal activities.

Four undescribed cycloartane-type triterpenoids (1-4) and seven undescribed steroids (6-12), along with five known analogues (5 and 13-16), were isolated from the leaves of Trichilia connaroides. Their structures were identified based on the NMR data and HRESIMS, and the absolute configurations were determined through single-crystal X-ray diffraction analysis, Mosher's method, and ECD calculations. The multidrug resistance (MDR) reversal activities of all the isolates were assessed, and compounds 10 and 11 showed significant activities to reverse the MDR of MCF-7/DOX cells with IC50 values of 2.90 and 3.76 µM, respectively. These bioactive compounds may bring fresh insights into the research and development of MDR reversal agents.

New Guaiane-Type Sesquiterpenoids Biscogniauxiaols A-G with Anti-Fungal and Anti-Inflammatory Activities from the Endophytic Fungus Biscogniauxia Petrensis.

Seven undescribed guaiane-type sesquiterpenoids named biscogniauxiaols A-G (1-7) were isolated from the endophytic fungus Biscogniauxia petrensis on Dendrobium orchids. Their structures were determined by extensive spectroscopic analyses, electronic circular dichroism (EC) and specific rotation (SR) calculations. Compound 1 represented a new family of guaiane-type sesquiterpenoids featuring an unprecedented [5/6/6/7] tetracyclic system. A plausible biosynthetic pathway for compounds 1-7 was proposed. The anti-fungal, anti-inflammatory and multidrug resistance reversal activities of the isolates were evaluated. Compounds 1, 2 and 7 exhibited potent inhibitory activities against Candida albicans with MIC values ranging from 1.60 to 6.30 µM, and suppressed nitric oxide (NO) production with IC50 ranging from 4.60 to 20.00 µM. Additionally, all compounds (100 µg/mL) enhanced the cytotoxicity of cisplatin in cisplatin-resistant non-small cell lung cancer cells (A549/DDP). This study opened up a new source for obtaining bioactive guaiane-type sesquiterpenoids and compounds 1, 2, and 7 were promising for further optimization as multifunctional inhibitors for anti-fungal (C. albicans) and anti-inflammatory purposes.

Dynamic covalent nano-networks comprising antibiotics and polyphenols orchestrate bacterial drug resistance reversal and inflammation alleviation.

New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms. This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks (aDCNs) composing antibiotics bearing multiple primary amines, polyphenols, and a cross-linker acylphenylboronic acid. Mechanistically, the iminoboronate bond drives the formation of aDCNs, facilitates their stability, and renders them highly responsive to stimuli, such as low pH and high H2O2 levels. Besides, the representative A1B1C1 networks, composed of polymyxin B1(A1), 2-formylphenylboronic acid (B1), and quercetin (C1), inhibit biofilm formation of drug-resistant Escherichia coli, eliminate the mature biofilms, alleviate macrophage inflammation, and minimize the side effects of free polymyxins. Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model. The facile synthesis, excellent antimicrobial performance, and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines.

Ginsenoside Rb1 for overcoming cisplatin-insensitivity of A549/DDP cells in vitro and vivo through the dual-inhibition on two efflux pumps of ABCB1 and PTCH1.

BACKGROUND: The multi-drug resistance is an inherent weakness in the chemotherapeutics of non-small cell lung cancer occurring frequently all over the world. Clinically, ginseng and Chinese medicinal prescriptions including ginseng usually used as anti-tumor adjuncts due to its characteristic of qi-invigorating, which could improve the curative effect of chemotherapy drugs and reduce their toxic side effects. Triterpenoid saponins are the crucial active ingredients in Panax ginseng, and Ginsenoside Rb1 is of the highest quantities. However, the research on the tumor drug-resistance reversal effect and mechanism of ginsenoside Rb1 is still not clear. PURPOSE: This study aimed to systematically estimate the reversal activity of Ginsenoside Rb1 on cisplatin-insensitivity of A549/DDP cells and to reveal its prospective molecular mechanism. METHODS: MTT assay were conducted to evaluate the reversal activity on cisplatin-insensitivity of A549/DDP cells of Ginsenoside Rb1in vitro, and the behavior was also studied by establishing a subcutaneous transplanted tumor model of A549/DDP in BALB/c-nu mice. In addition, P-gp ATPase activity assay, cisplatin accumulation assay, Annexin V-FITC apoptosis assay, real-time qPCR analysis and western blotting analysis were used to clarify the potential mechanism. RESULTS: Ginsenoside Rb1 could effectively reverse the cisplatin-resistance of A549/DDP in vitro and vivo. And after the co-treatment of Ginsenoside Rb1 plus cisplatin, the accumulation of cisplatin increased in A549/DDP cells, which was accompanied with the down-regulation of the mRNA and protein expression levels of ABCB1, SHH, PTCH1 and GLI2. Besides, the apoptosis-inducing ability of cisplatin improved by the relative regulation on the protein expression level of Bax and Bcl-2. Far more importantly, the changes of CYP3A4 mRNA and protein levels were not significant. CONCLUSION: Ginsenoside Rb1 could increase the concentration of intracellular cisplatin and improve the insensitivity for cisplatin on A549/DDP cells. Even better, there was perhaps no unpredictable CYP3A4-mediated pharmacokinetic interactions after the combination of Ginsenoside Rb1 plus cisplatin. Ginsenoside Rb1 was a probable reversal agent for the cisplatin-insensitivity of A549/DDP cells, with a bifunction of inhibiting the efflux of two drug pumps (P-gp and PTCH1) by targeting ABCB1 and Hedgehog (Hh) pathway. In general, this research laid the groundwork for the development of a new reversal agent for the cisplatin-insensitivity of NSCLC.

No life-history cost of tebufenozide resistance in the smaller tea tortrix moth.

BACKGROUND: Tebufenozide is widely used to control populations of the smaller tea tortrix, Adoxophyes honmai. However, A. honmai has evolved resistance such that straightforward pesticide application is an untenable long-term approach for population control. Evaluating the fitness cost of resistance is key to devising a management strategy that slows the evolution of resistance. RESULTS: We used three approaches to assess the life-history cost of tebufenozide resistance with two strains of A. honmai: a tebufenozide-resistant strain recently collected from the field in Japan and a susceptible strain that has been maintained in the laboratory for decades. First, we found that the resistant strain with standing genetic variation did not decline in resistance in the absence of insecticide over four generations. Second, we found that genetic lines that spanned a range of resistance profiles did not show a negative correlation between their LD50 , the dosage at which 50 % of individuals died, and life-history traits that are correlates of fitness. Third, we found that the resistant strain did not manifest life-history costs under food limitation. Our crossing experiments indicate that the allele at an ecdysone receptor locus known to confer resistance explained much of the variance in resistance profiles across genetic lines. CONCLUSION: Our results indicate that the point mutation in the ecdysone receptor, which is widespread in tea plantations in Japan, does not carry a fitness cost in the tested laboratory conditions. The absence of a cost of resistance and the mode of inheritance have implications for which strategies may be effective in future resistance management efforts. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Synergistic Combination of the Total Steroidal Saponins from the Berries of Black Nightshade and Adriamycin to Overcome Leukemia Multidrug Resistance.

The berries of black nightshade (Solanum nigrum L.) are consumed as a favorite fruit in some regions and have been reported to possess a range of biological activities. Previous studies have found that the steroidal saponins from the berries of S. nigrum (SN) showed potential antileukemic activity, although the underlying mechanism remains to be revealed. This study investigated the effects and mechanisms of SN in combination with adriamycin to reverse leukemia multidrug resistance in vivo and in vitro. The results indicated that the combination of SN and adriamycin displayed enhanced suppression ability both in vitro and in vivo by the modulation of drug efflux proteins. Further study revealed that SN and adriamycin co-treatment induced cell apoptosis in K562/ADR cells through caspase pathways and autophagy through the PI3K/Akt/mTOR and MAPK signaling pathway. This study provides a new prospect of the berries of black nightshade in multidrug resistance therapy of cancer.

Jatrophane diterpenoids from Euphorbia microcarpa (prokh.) krylov with multidrug resistance modulating activity.

Eight undescribed jatrophane diterpenoids, namely euphomicrophane A-H, together with thirteen known diterpenes were isolated from the whole plant extracts of Euphorbia microcarpa (Prokh.) Krylov. Among them, euphomicrophane C and F were possessed the endo-type core structure that naturally rarely appeared. The structures of the purified undescribed compounds were established by extensive spectroscopic and spectrometric analysis, and the single-crystal X-ray diffraction analysis was used to determine the absolute configuration of euphomicrophane E, elusone A and euphorbesulin G. All the isolates were screened for their reversal abilities on P-glycoprotein-mediated multidrug resistant cancer cell line MCF-7/ADR. Compounds euphomicrophane G-H and 3ß,7ß,8α,9α,15ß-pentaacetoxy-5ß-benzoyloxyjatropha-6(17)-11E-dien-14-one were showed potential chemoreversal effect with reversal fold values 18.67, 17.15, and 16.76 at a concentration of 10.0 µM, being equal to or stronger than the positive drug verapamil (16.68).

Ingol, ent-atisane, and stachane-type diterpenoids from Euphorbia deightonii with multidrug resistance reversing activity.

Nine previously undescribed ingol-type diterpenoid polyesters with eighteen known ingol esters, two ent-atisane, and one stachane diterpenoid were isolated from the methanol extract of Euphorbia deightonii Croizat. The structures were established by extensive spectroscopic analysis involving 1D (1H, 13C J-modulation) and 2D NMR experiments, HRESIMS measurements, and the comparison of the spectroscopic data with reported literature values. The cytotoxic concentrations of 13 isolated compounds were determined, and the compounds were investigated for multidrug resistance modulating activity on an L5178 mouse lymphoma cell line using a rhodamin 123 accumulation assay. Six ingol esters demonstrated the significant inhibition of P-glycoprotein, while the two ent-atisane diterpenoids were found to be inactive. The measured activities allowed to establish some structure-activity relationships. Notably, lower and higher-type diterpenoids simultaneously occurred in E. deightonii.

Therapeutic implication of carbon monoxide in drug resistant cancers.

Drug resistance is the major obstacle that undermines effective cancer treatment. Recently, the application of gas signaling molecules, e.g., carbon monoxide (CO), in overcoming drug resistance has gained significant attention. Growing evidence showed that CO could inhibit mitochondria respiratory effect and glycolysis, two major ATP production pathways in cancer cells, and suppress angiogenesis and inhibit the activity of cystathionine ß-synthase that is important in regulating cancer cells homeostasis, leading to synergistic effects when combined with cisplatin, doxorubicin, or phototherapy, etc. in certain resistant cancer cells. In the current review, we attempted to have a summary of these research conducted in the past decade using CO in treating drug resistant cancers, and have a detailed interpretation of the underlying mechanisms. The critical challenges will be discussed and potential solutions will also be provided. The information collected in this work will hopefully evoke more effects in using CO for the treatment of drug resistant cancers.

Chidamide Reverses Fluzoparib Resistance in Triple-Negative Breast Cancer Cells.

Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance is a new challenge for antitumor therapy. The purpose of this study was to investigate the reversal effects of chidamide on fluzoparib resistance, a PARPi, and its mechanism of action. A fluzoparib-resistant triple-negative breast cancer (TNBC) cell line was constructed, and the effects of chidamide and fluzoparib on drug-resistant cells were studied in vitro and in vivo. The effects of these drugs on cell proliferation, migration, invasiveness, the cell cycle, and apoptosis were detected using an MTT assay, wound-healing and transwell invasion assays, and flow cytometry. Bioinformatics was used to identify hub drug resistance genes and Western blots were used to assess the expression of PARP, RAD51, MRE11, cleaved Caspase9, and P-CDK1. Xenograft models were established to analyze the effects of these drugs on nude mice. In vivo results showed that chidamide combined with fluzoparib significantly inhibited the proliferation, migration, and invasiveness of drug-resistant cells and restored fluzoparib sensitivity to drug-resistant cells. The combination of chidamide and fluzoparib significantly inhibited the expression of the hub drug resistance genes RAD51 and MRE11, arrested the cell cycle at the G2/M phase, and induced cell apoptosis. The findings of this work show that chidamide combined with fluzoparib has good antineoplastic activity and reverses TNBC cell resistance to fluzoparil by reducing the expression levels of RAD51 and MRE11.

Iloneoside, an antimalarial pregnane glycoside isolated from Gongronema latifolium leaf, potentiates the activity of chloroquine against multidrug resistant Plasmodium falciparum.

The rapid spread of drug resistant malaria parasites has necessitated the search for novel antimalarials and chemosensitizers capable of reversing drug resistance in the parasites. A number of studies have revealed the resistance reversal activities of pregnane glycosides and the antimalarial activity of a pregnane glycoside obtained from Gongronema species. However, the pregnane (2) and pregnane glycosides (1, 3-4) isolated from Gongronema latifolium leaf have not been evaluated for these activities. This study was therefore carried out to evaluate the antiplasmodial and chloroquine resistance reversal activities of a pregnane and three pregnane glycosides isolated from G. latifolium leaf in vitro. The compounds were evaluated for their inhibitory activities against P. falciparum 3D7 (a chloroquine-sensitive strain) and P. falciparum W2 (a chloroquine-resistant clone) in vitro. The activities of chloroquine in separate combination with each of the compounds against P. falciparum W2 were also evaluated. Moreover, the interaction of the active compounds (1 and 4) with selected P. falciparum proteins (PfProteins) were evaluated in silico. The results revealed that only 1 and 4 were active against P. falciparum 3D7 and P. falciparum W2. Also, 2 and 3 did not exhibit chloroquine resistance reversal activity. Activity of chloroquine against P. falciparum W2 was potentiated by 1 by 3200% at concentrations higher than 0.625 µg/mL. Also, 1 and 4 demonstrated similar binding patterns and higher binding tendencies to the selected PfProteins compared to chloroquine. Thus, 1 (iloneoside) is an antimalarial pregnane glycoside which can potentiate the activity of chloroquine against multidrug resistant P. falciparum.