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. 2023 May 25;14(8):1400–1409. doi: 10.1039/d3md00155e

Progress in the discovery and development of small molecule methuosis inducers

Tao Ye a, Peipei Shan b,✉, Hua Zhang a,✉
PMCID: PMC10429883  PMID: 37593581

Abstract

Current cancer chemotherapies rely mainly on the induction of apoptosis of tumor cells, while drug resistance arising from conventional chemicals has always been a big challenge. In recent years, more and more new types of cell deaths including methuosis have been extensively investigated and recognized as potential alternative targets for future cancer treatment. Methuosis is usually caused by excessive accumulation of macropinosomes owing to ectopic activation of macropinocytosis, which can be triggered by external stimuli such as chemical agents. Increasing reports demonstrate that many small molecule compounds could specifically induce methuosis in tumor cells while showing little or no effect on normal cells. This finding raises the possibility of targeting tumor cell methuosis as an effective strategy for the prevention of cancer. Based on fast-growing studies lately, we herein provide a comprehensive overview on the overall research progress of small molecule methuosis inducers. Promisingly, previous efforts and experiences will facilitate the development of next-generation anticancer therapies.

The discovery and development of small molecule methuosis inducers and their modes of action were summarized for the first time.graphic file with name d3md00155e-ga.jpg

Introduction

Methuosis is a relatively new way of cell death that was first named after the Greek word methuo in 2008.1 The initial study on methuosis could be traced back to the work by Chi et al. in 1999,2 when they found that Ras mutation in human glioblastoma and gastric cancer cells caused a non-apoptotic cell death characterized by the accumulation of massive vacuoles within the cytoplasm. It was subsequently proven that the vacuoles in the tumor cells were macropinosomes produced by unregulated macropinocytosis.1,3,4 The accumulation and fusion of macropinosomes eventually led to the formation of vacuoles in the cytoplasm, resulting in the rupture of the cell membrane and thus cell death.

Macropinocytosis is a non-specific endocytic pathway independent of grid proteins and plays a key role in the extracellular nutrient uptake and antigen presentation of eukaryotic cells.5–7 In normal circumstances, it promotes the non-selective internalization of extracellular fluid in various types of cells to satisfy different physiological requirements.8 For example, it helps tumor cells survive in a nutrient-deficient environment9 and enhances their resistance to anticancer drugs.10 However, hyper-activated macropinocytosis due to either internal (e.g. Ras mutation) or external (e.g. chemical stimuli) factors will result in abnormal cell death (methuosis).11,12 In recent years, there has been a significant increase in reports on the correlation of mocropinocytosis with tumorgenesis, revealing its important role in the growth, proliferation and drug resistance of a number of tumor cells. Meanwhile with increasing understanding toward this interesting biological process, methuosis caused by macropinocytosis has been gradually recognized as a new promising target for cancer prevention.

Among all the factors that lead to methuosis by disturbing macropinocytosis, small molecule chemicals have attracted more and more attention from researchers especially medicinal chemists in the drug discovery field. A preliminary literature retrieval (PubMed, Web of Science, SciFinder databases, etc.) revealed a rapidly growing number of publications on small molecule methuosis inducers in the last decade especially the past five years, whereas there are no review articles summarizing the past advances regarding these small molecules as potential new types of anticancer agents. Following a brief introduction of the major causes leading to methuosis, the current paper presents a comprehensive overview on the discovery and development of both natural products and synthetic compounds as methuosis inducers, as well as their primary mechanisms. Hopefully, this review will serve as a reference and provide new ideas for discovering and designing new anticancer therapeutics.

Failure of macropinosome recycling leads to methuosis

A macropinosome is a kind of endosome formed by internalization of extracellular nutrients, antigens and other solute molecules during macropinocytosis, and normally there is a complete recycling system for macropinosomes after they fulfil their roles.13 Many cell types, including tumor cells and immune cells, have the same molecular mechanism of macropinocytosis under normal regulation.12,14–17 In general, ruffle membrane/lamellipodia form following the activation of Ras protein and further develop into macropinocytic sinks. Then the macropinocytic sinks close to form macropinosomes through the successive activation of a number of GTPases and phosphoinositides. After entering the cytoplasm, macropinosomes become mature by recruiting early endosomal proteins Rab5 and EEA1. Under normal conditions, some mature macropinosomes will recruit late endosomal proteins Rab7 and LAMP1 and then fuse with lysosomes, and the others are recycled directly by the cell membrane.18–20 However, under abnormal circumstances such as Ras overexpression or chemical stimulation, macropinosomes cannot recruit the above-mentioned early endosomal proteins, and their fusion with lysosomes and recycling by the cell membrane are thus prevented,21 which would cause abnormal homotypic fusion to form giant vacuoles, resulting in the rupture of the cell membrane and thus cell death (methuosis).

H-Ras overactivation induces methuosis

The occurrence of methuosis involves different mechanisms, the mostly studied one of which is the activation of the Rac1–Arf6 signaling pathway caused by the overexpression of Ras.3 The earliest evidence of methuosis via H-Ras hyperactivation was found in glioblastoma and gastric cancer with Ras mutation.2,22 Later, Maltese and colleagues investigated the specific mechanism by which H-Ras overactivation induces methuosis in glioblastoma.1,3,4 In detail, H-Ras first turns Rac1 into the active form which subsequently binds to GIT1 and the latter further interacts with Arf6 to form a Rac1–GIT1–Arf6 complex, which results in the loss of Arf6 activity.3,23,24 Normally, Arf6 controls macropinosomes' recycling and fusion with lysosomes.25,26 Therefore, the formation of the above-mentioned complex would prevent macropinosomes from recycling back to the cell membrane and fusing with lysosomes. In addition, the increased expression of the H-Ras gene also causes the decrease of the ATP level and mitochondrial membrane potential (MMP) in glioblastoma,1,24,27 which affects the metabolic function of mitochondria and prevents the ATP-mediated fusion of macropinosomes with lysosomes. Both aforementioned mechanisms would result in continuous macropinosome accumulation in the cytoplasm, eventually leading to cell rupture and death (Fig. 1). Unfortunately, the molecular mechanism of how the fusion of macropinosomes with lysosomes is inhibited in methuosis is still unclear.

Fig. 1. Two H-Ras related pathways leading to methuosis.

Fig. 1

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Small molecule methuosis inducers

Since the discovery of methuosis, it has been found that many small molecules including both natural products and synthetic compounds can induce methuosis and have been identified as potential leads for anticancer drugs. It is worth noting that more than half of small molecule methuosis inducers show low or no toxicity to normal cells, which is a tremendous superiority to traditional chemotherapies. All the inducers reported so far, as well as their origins, tested cancer cells and possible mechanisms, are listed in Table 1. A more detailed introduction on these small molecules will be presented below.

A list of reported small molecule methuosis inducers and their basic information.

Name Source Cancer cell Mechanism
Bacoside A Bacopa monnieri LN229, U87MG, U251 Increases cytoplasmic osmotic pressure by CaMKIIA
Jaspine B Pachastissamine sp. and Jaspis sp. HGC-27, A549 Associated with the activation of AMPK
Meridianin C Aplidium meridianum YD-10B Reduces the level of the negative regulator of macropinocytosis DKK-3
UAD 17 Structural modification from ursolic acid HeLa, HepG2, HT1080, MCF-7, SK-N-MC Not reported
Tubeimoside 1 Bolbostemma paniculatum SW480 Recruits LC3-II protein, stimulates macropinocytosis hyperactive
Matrine Sophora flavescens DLD-1 Lower ATP levels
Isobavachalcone Psoralea corylifolia, Angelica sinensis and Broussonetia papyrifera NB4, U937 Not reported
Epimedokoreanin C Epimedium koreanum NCl-H292, A549 Lower the ratio of Arf6/Rac1
Spiropachysine A Pachysandra axillaries MHCC-97H Activates the Ras–Rac1 signaling pathway
Bacillomycin Lb Bacillus amyloliquefaciens MCF-7, MDA-MB-231-Luc, 4T1, SMMC-7721, B16 Not reported
Trehalose Natural source (details not mentioned) U373-MG May be related to Ras overactivation
DMBP Radula constricta A549, PANC-1 Inhibits lysosomal fusion with macropinosomes
Maduramicin Actinomadura rubra LMH, H9c2 Activates the Ras–Rac1 signaling pathway, reduces ATP levels, and increases LDH
MIPP and its analogues Commercial compound library U251, LN229, U2OS, MCF7, SW480, PANC-1 Inhibits the ability of macropinosomes to fuse with lysosomes and activates the JNK1/2 pathway
Vacquinol-1 Commercial compound library Glioblastoma May be associated with Ras–Rac1–MKK4 activation, in addition to inhibiting the fusion of macropinosomes with lysosomes and reducing the ATP content
5-Iodoindole Commercial compound library Nematode embryonic cells Increase osmotic pressure
CX-4945 Commercial source HuCCA-1, CCLP-1, KKU-M213, MMNK-1, AKN-1 Not reported
CX-5011 Not mentioned (likely commercial source) HepG2, GN11, MDA-MB-231, HEK293T Activates the Ras–Rac1 signaling pathway
WJ-644A Lab synthesis PC3 By activating unfolded protein reactions
AXL degraders 20/22 Lab synthesis MDA-MB-231, MCF-7, 4T1 Activates the Ras–Rac1 signaling pathway
DZ-514/JH530 Lab synthesis HCC1806, HCC1937, MDA-MB-468 Activates the ROS–MKK4–p38 signaling pathway
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Natural products and their derivatives as methuosis inducers

The structures of natural methuosis inducers collected in this paper are shown in Fig. 2. Triterpenoids and alkaloids occupy a big proportion of the compound classes, and other structural types include lipid, oligosaccharide, polyketide, cyclopeptide and phenolic compounds. Most of them show the characteristics of low toxicity and high efficacy and could serve as lead structures for further development.

Fig. 2. Structures of natural small molecule methuosis inducers.

Fig. 2

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Bacoside A

In 2017, John and coworkers28 demonstrated that the triterpenoid saponin, bacoside A from a traditional Indian medicinal plant Bacopa monnieri,29 showed antitumor activity against glioblastoma cell lines (LN229, U87MG and U251) via inducing methuosis. In terms of mechanism, bacoside A caused a large amount of calcium release from the smooth endoplasmic reticulum to the cytoplasm by hyperphosphorylation of calcium/calmodulin-dependent protein kinase IIA, which increased the osmotic pressure in the cytoplasm.28 The high intracellular osmotic pressure then stimulated excessive macropinocytosis uptake of extracellular substances, resulting in cell hypertrophy and vacuole accumulation, accompanied by cell roundness and cell membrane rupture and the final non-apoptotic death of glioblastoma cells. Further studies revealed that bacoside A at the same concentration did not cause any phenotypic change in human normal keratinocytes, indicating its potential as a candidate for the development of new antitumor chemotherapy. Of note, although the authors provided a chemical structure in the report, this commercially available ‘compound’ had been identified to be a mixture of four structurally close triterpenoid glycosides.30,31

Jaspine B

Jaspine B, a sphingolipid analogue, is a marine natural product obtained from sponges Pachastissamine sp. and Jaspis sp., and it has been reported to induce apoptotic and autophagy-mediated cell death in a number of human and mouse cancer cell lines.32,33 However, in Cingolani and colleagues' report jaspine B was also identified as a cell methuosis inducer.34 Briefly, it could induce the formation of single-membrane vacuoles in the cytoplasm in a time and dose-dependent manner, which was different from the double-membrane autophagy process and independent of its inhibitory activity against ceramide synthase. Interestingly, the vacuoles of normal HEK293T cells caused by the stimulation of jaspine B would gradually disappear as time went on (after 24 h), indicating that its induced methuosis has a certain selectivity toward the tested tumor cells. In a recent report by Bielsa et al.,35 they further proved that the cavitation induced by jaspine B was related to the activation of adenosine 5′-monophosphate activated protein kinase.

Meridianin C

Meridianin C is a brominated indole alkaloid initially isolated from the marine tunicate Aplidium meridianum and showed cytotoxicity toward LMM3 (murine mamarian adenocarcinoma cell line).36 It was also recorded to have anti-proliferative activity against human breast (MCF-7), cervical (HeLa) and leukemia (MV4-11) cancer cells in later documents.37,38 Park et al. reported in 2017 that this indole derivative could reversibly induce the methuosis of human oral cancer cells (YD-10B).39 Detailed mechanism investigation revealed that the effect of meridianin C on YD-10B cells was achieved by reducing the cellular level of Dickkopf-related protein-3 (DKK-3) which is a negative regulator of macropinocytosis. Excitingly, low concentration (1 μM) treatment by this molecule only induced vacuole formation in YD-10B cells but had no cytotoxicity toward normal gingival fibroblasts.

Ursolic acid derivative 17

A series of triterpenoid derivatives by structural modification on ursolic acid were obtained by Li′s and Wei's research groups in 2017,40 and several compounds were found to induce vacuoles in an array of human tumor cell lines including HeLa, HepG2, HT1080, MCF-7 and SK-N-MC. Among them, UAD17 was subjected to further studies in HeLa cells, which demonstrated that the cancer cell death caused by this molecule was through the hyperstimulation of macropinocytosis. Moreover, UAD17 had no obvious effect on normal cells such as human skin fibroblasts (HDF) and mouse myoblasts (C2C12). Nonetheless, the detailed molecular mechanism was not further investigated in this report.

Tubeimoside 1

Tubeimoside 1 is a pentacyclic triterpenoid saponin originally discovered from the traditional Chinese medicinal plant Bolbostemma paniculatum and exerted antitumor effects both in vitro and in vivo.41 In 2018, Sun and coworkers reported that tubeimoside 1 could stimulate the overproduction of macropinocytosis by recruiting LC3-II protein and thus induce methuosis in SW480 colorectal cancer cells.42 In addition, it also exhibited a synergistic antitumor effect by increasing the uptake of the clinical drug fluorouracil.

Matrine

Matrine, a quinolizidine alkaloid separated from a well-known herbal species Sophora flavescens, is a commercially available insecticide in China. Li and collaborators first predicted by the drugCIPHER-CS method that matrine may have the ability to induce methuosis and regulate ATP metabolism.43 Subsequently, they experimentally demonstrated that this alkaloid down-regulated the ATP level of human colorectal adenocarcinoma epithelial cells (DLD-1) in a concentration-dependent manner and induced DLD-1 cytoplasm to produce large vesicles with methuosis characteristics.

Isobavachalcone

Isobavachalcone belongs to the big family of flavonoids and exists in the seeds of Psoralea corylifolia, Angelica sinensis and Broussonetia papyrifera, with a variety of bioactivities.44 The work by Yang et al. uncovered that treatment of this chalcone compound for 72 h could lead to methuosis in NB4 and U937 leukemic cells but not in normal peripheral blood cells.45 More interestingly, processing with macropinocytosis inhibitors (bafilomycin A, chloroquine or MK2206) on pretreated NB4 and U937 cells by isobavachalcone for 24 h could indeed suppress the formation of macropinosomes, but the cell activity also decreased. These findings suggest that macropinosomes may play a role in saving cells in the early stage of methuosis induced by isobavachalcone.

Epimedokoreanin C

In 2021, Ren and colleagues obtained a series of prenylated flavonoids from the leaves of a traditional Chinese medicine, Epimedium koreanum.46 Among them, epimedokoreanin C was found to induce methuosis in lung cancer cell lines NCl-H292 and A549, by down-regulating the ratio of Arf6/Rac1 to form cytoplasmic vacuoles. In addition, this methuosis inducer had no significant effect on normal bronchial epithelial cells 16HBE, and it could also enhance the sensitivity of the tested cancer cells to chemotherapeutic drugs doxorubicin and etoposide.

Spiropachysine A

Spiropachysine A is a steroidal alkaloid isolated from a Chinese ethnic medicine, Pachysandra axillaries.47–49 It is interesting to note that the nomenclature and stereochemistry of this compound appear to be ambiguous in the literature. However, Fang et al.50 investigated its antitumor activity and potential mechanism against hepatocellular carcinoma both in vitro and in vivo. Spiropachysine A was first observed to inhibit the cell growth of a panel of human cancer cells (MDA-MB-231, MHCC-97H, HCT-116, BGC-823, HEL and SH-SY5Y cells). In a subsequent work, the methuosis-inducing effects of this alkaloid in both MHCC-97H cells and MHCC-97H transplanted nude mice were studied systematically, and the mechanism was demonstrated to be via the activation of the Ras–Rac1 signaling pathway.

Bacillomycin Lb

Bacillomycin Lb is a cyclic lipopeptide isolated from Bacillus amyloliquefaciens X030 by Lu et al.51 It could induce methuosis in breast cancer cells including MCF-7, MDA-MB-231-Luc (human) and 4T1 (mouse), as well as human liver cancer cell SMMC-7721 and mouse melanoma cell B16, but it had no significant effect on normal breast cell MCF-10A. The fatty acid chain was then proven to be the key fragment for its methuosis inducing activity. Further investigations revealed that nanoparticles formed from bacillomycin Lb at a low concentration (6 μM) could be internalized by breast cancer cells to cause cytoplasmic vacuolization. Lastly, the methuosis inducing effect of this lipopeptide was also verified in vivo in MDA-MB-231-Luc transplanted mice, without showing obvious side effects on the kidney, liver and spleen.

Trehalose

Trehalose is a disaccharide that exists widely in natural organisms and is considered to be a ‘generally recognized as safe’ nutritional supplement by FDA.52 Researchers from Maellaro's team recently discovered that trehalose could induce methuosis but not autophagy in U373-MG glioblastoma cells.53 In contrast, it was found to only induce autophagy in another macropinocytosis-deficient glioblastoma cell line, T98G, indicating that these two processes (methuosis and autophagy) appeared to act in a mutually exclusive manner. This may be related to the coincident AMPK–mTOR1 signaling pathway in both methuosis and autophagy.

DMBP

Methyl 2,4-dihydroxy-3-(3-methyl-2-butenyl)-6-phenethylbenzoate (DMBP) is a prenylated bibenzyl compound that was obtained from the Chinese liverwort Radula constricta and identified as an anticancer agent by Lou's group.54 The authors confirmed that DMBP could induce methuosis and inhibit autophagy to exert its anti-tumor effect. Mechanistically, DMBP inhibited the fusion of macropinosomes and lysosomes by inhibiting a VPS41 subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, leading to methuosis in human lung cancer cell A549 and pancreatic cancer cell Panc-1. In addition, DMBP effectively suppressed the metastasis of B16-F10 cancer cells in a mouse metastatic melanoma model.

Maduramicin

Maduramicin is a natural polyketide antibiotic originally isolated from Actinomadura rubra and is currently mainly used as a pesticide in poultry industry.55 Gao et al. proved that the non-apoptotic death of primary chicken embryo fibroblasts and chicken hepatoma cells (LMH) induced by maduramicin was methuosis.56 Further exploration in rat cardiomyocytes (H9c2) revealed that maduramicin activated the Ras–Rac1 signal pathway at mRNA and protein levels leading to macropinocytosis imbalance, decreased intracellular ATP levels and increased LDH.57

Synthetic small molecules as methuosis inducers

The majority of synthetic methuosis inducers reported to date arise from screening of existing compound libraries especially of commercial sources, and their structures are provided in Fig. 3. Among these synthetic molecules, CX-4945 with the trivial name ‘Silmitasertib’ is currently in clinical trial, which will surely inspire further efforts in the study of related analogues.

Fig. 3. Structures of synthetic small molecule methuosis inducers.

Fig. 3

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MIPP and its analogues

3-(5-Methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propen-1-one (MIPP) and its 5-brominated analogue (BMIPP), available from a commercial compound library, were first reported by Overmeyer et al. to cause extreme vacuolization in the cytoplasm of glioblastoma cells (U251), and MIPP was chosen for further studies owing to its better effect.27 Subsequent investigations showed that MIPP induced dramatic cytoplasmic vacuolization in an array of other cancer cells including drug-resistant glioblastoma, and the list comprised glioma (LN229), osteosarcoma (U2OS), and breast (MCF7), colon (SW480) and pancreatic (PANC-1) carcinoma cells. Further work revealed that the mode of action of MIPP appeared to target steps in the endosomal trafficking pathway involving Rab5 and Rab7. In a later report,58 researchers from the same team synthesized additional MIPP analogues and found six more compounds with similar vacuole-inducing activities, among which the 5-methoxy derivative (MOMIPP) displayed the best activity in the MTT cell viability assay. These authors further demonstrated that methuosis induced by MIPP or MOMIPP did not need the activation of Rac1 and the inactivation of Arf6 but was actualized by reducing the level of early endosomal protein Rab5, recruiting late endosomal protein Rab7 prematurely, and inhibiting the maturation of macropinosomes and their ability to fuse with lysosomes. After seven years, they further reported that MOMIPP could selectively activate the JNK1/2 stress kinase pathway, leading to phosphorylation of c-Jun, Bcl-2 and Bcl-xL.59

Vacquinol-1

In 2014, vacquinol-1 was picked out from a synthetic compound pool as a methuosis inducer for glioblastoma.60 The cell death induced by this alkaloidal compound may be related to the activation of downstream MAP kinase 4 (MKK4) by Ras/Rac-1, and it was also demonstrated to show no toxicity to normal mouse embryonic stem cells and fibroblasts. Of note, this seemingly pioneering work had been retracted by the authors with the exact reason being unknown. Further work by Sander et al. showed that exogenous ATP inhibited vacquinol-1-induced glioblastoma methuosis by activating TRPM7 and P13K, suggesting that the up-regulation of ATP levels may interfere with the related cell death pathway.61 Then Ernfors's group validated the mechanism of cavitation in the methuosis caused by vacquinol-1.62 On the one hand, vacquinol-1 inhibited the fusion of macropinosomes, corpuscles and lysosomes through direct interaction with calmodulin; on the other hand, it also stimulated the formation of acidic vesicle organelles by activating V-ATPase, which increased the consumption of ATP.

5-Iodoindole

In 2017, Rajasekharan and coworkers tested 34 indole derivatives from commercial sources and identified four compounds as good insecticidal agents against Bursaphelenchus xylophilus (pinewood nematodes).63 The most active, 5-iodoindole, was found to induce methuosis in nematode embryonic cells and caused embryonic development malformation and organ destruction of the pest. The methuosis-inducing mechanism of 5-iodoindole was also probed by subsequent molecular docking experiments. It may be by increasing the osmolality and stimulating the cytoplasm to produce vacuoles, inducing methuosis.

CX-4945 and CX-5011

Lertsuwan et al. found in 2018 that the protein kinase CK2 (previously known as casein kinase II) inhibitor CX-4945 could induce vacuolization in the cytoplasm of cholangiocarcinoma cells (HuCCA-1, CCLP-1, KKU-M213, MMNK-1 and AKN-1),64 in a time and dose dependent manner, and induce methuosis in a CK2-independent mechanism. In 2020, D'Amore and Salvi's research team further investigated CX-5011 which is a structural congener of CX-4945.65 The specific mode of action of CX-5011-induced methuosis was not fully disclosed, but there was evidence that CX-5011 could stimulate Rac1 activation, which is a typical H-Ras-induced methuosis mechanism. The accumulation of Rab7 was also observed by confocal microscopy in a zebrafish model, indicating that CX-5011 could induce the production of macropinosomes and induce methuosis in vivo.

WJ-644A

WJ-644A, a quaternary ammonium salt of the isoquinoline alkaloid class, is reported as an activator of unfolded protein response(UPR).66 The research groups of Sun, Yang and Ding determined that WJ-644A can induce methuosis in castration-resistant prostate cancer (PC3) and its mouse model, but has it low toxicity to normal cells (RWPE-1, L02) and cannot cause cytoplasmic vacuolization of normal cells. Mechanistically, this study has clearly confirmed that WJ-644A induces methuosis by activating the UPR.

AXL degraders 20 and 22

Compounds 20 and 22 were initially designed and synthesized as anexelekto (AXL, a receptor tyrosine kinase) degraders by Qian's research group;67 meanwhile, they were observed to induce the formation of cytoplasmic vacuoles and trigger methuosis in MDA-MB-231, 4T1 and MCF-7 breast cancer cells. Meanwhile, they displayed no toxicity to human normal breast cancer cell MCF-10A and gastric mucosal epithelial cell GES-1. A further mechanism study revealed that the vacuole formation caused by the two compounds was mediated by H-Ras activation, which could be attenuated by suppression of the downstream regulator Rac1.

DZ-514 and JH530

Compound DZ-514 was recognized as the most active molecule from 58 synthetic N-phenyl-4-pyrimidine diamine derivatives that were designed for the prevention of triple negative breast cancer,68 and it exhibited strong cytotoxicity against HCC1806 and MDA-MB-468 cells at very low concentrations. In addition, DZ-514 caused concentration and time-dependent accumulation of cytoplasmic vacuoles in the tested cancer cells but did not cause vacuolation in immortalized breast epithelial cells (184B5 cells), indicating that DZ-514-induced vacuolization was specific. Most importantly, methuosis induced by DZ-514 was partially mediated through activation of the ROS-MKK4-p38 signalling pathway. DZ-514 also exhibits methuosis-inducing activity in a TNBC mouse xenograft model. Very recently, the same authors have also reported another analogue named JH530 which significantly induced methuosis in HCC1806, HCC1937 and MDA-MB-468 breast cancer cells,69 and the detailed molecular mechanism of JH530, though not mentioned in the new publication, should be the same as that of its congener, DZ-514, due to their high structural similarity.

Discussion and prospect

Resisting cell death is one of the hallmarks of cancer cells,70 and current chemotherapeutic regimens for cancer rely primarily on drugs that activate the apoptotic cell death pathway. To date, small molecules that induce apoptosis have been extensively and thoroughly studied for cancer treatment.71 Despite the significant progress achieved, there are still many challenges to be resolved. For instance, the majority of patients would develop resistance toward these small molecule anti-cancer drugs after a period of clinical use,72 and apoptosis dysregulation could be responsible for this drug resistance.73 In addition, most of the existing anticancer chemicals show low efficiency and various severe side effects. Therefore, discovery of new types of chemotherapies that trigger cell deaths other than apoptosis has gradually become a promising trend in the development of next-generation anticancer drugs. In addition to the methuosis described above, non-apoptotic deaths with similar vacuoles in the cytoplasm also include paraptosis and oncosis. Paraptosis is often accompanied by endoplasmic reticulum stress, as well as accumulation of wrong proteins that are mainly related to MAPK and Wnt/β-catenin pathways.74–76 Activation of PORIMIN (pre-oncosis receptor induced membrane injury) causes cell death, in which the endoplasmic reticulum and Golgi apparatus swell to form vacuoles due to perforin-1 and caspase-1.77,78 Ideally, cell death inducers to be developed in the future should at least partially overcome the existing drug resistance issues and achieve a better balance between efficacy and side effects.

Methuosis is a new form of non-apoptotic cell death that has recently been proposed as a target for designing new anticancer therapies.12 Studies indicate that methuosis may be strongly correlated with the proliferation and migration of a variety of tumor cells,59 and some work has clarified that the ectopic expression of activated Ras l could lead to the occurrence of methuosis and the C-Jun N-terminal kinase (JNK) signaling pathway also plays a key role in the methuosis process.1,59 In addition, data have shown that the PI3K–AKT signaling pathway has the function of regulating macropinocytosis,5,14 and its related protein PIKfyve can also regulate endocytosis-related pathways. Therefore, inhibition of PIKfyve could also induce abnormal vacuolization in cells,79 suggesting a potential role to induce methuosis in tumor cells. Nonetheless, the detailed relationship between methuosis and cancer development still remains unclear, and more efforts are thus required to explore the molecular mechanism of methuosis, which will surely facilitate future research seeking new approaches for cancer treatment. Meanwhile, quite a few small molecules that induce methuosis in various cancer cell types have been reported,27,80 and accumulating evidence demonstrates that small molecule methuosis inducers present good selectivity toward tumor cells while showing low toxicity and high efficiency, which opens a new door for future cancer prevention. However, based on the current limited knowledge on methuosis due to its short research history, the disadvantages of methuosis inducers as possible drug candidates still remain unclear and unexplored. As a key protein related to methuosis, Ras is frequently mutated in tumor cells and has been considered as an unsuitable drug target,2 which could be an issue in the development of new small molecule methuosis inducers.

In summary, this review briefly discusses the main causes of methuosis occurrence, as well as presents a comprehensive overview on the discovery and development of small molecule methuosis inducers. Continuing studies on methuosis as an alternative death pathway for cancer cells will help us better understand the molecular biological mechanism of cancer, and knowledge presented in the current report could serve as a reference for studying methuosis in cancers and for designing methuosis-targeting anticancer drugs in the future. Nevertheless, our comprehension toward the role of methuosis in cancers is still limited and the detailed mechanisms of how different small molecule methuosis inducers affect cancer cells have not been fully understood. With increasing understanding on oncobiology and the evolution of new drug research and development technologies, we believe that more new small molecule inducers that could trigger methuosis will be discovered and their modes of action will also be explored and characterized. Promisingly in the near future, these efforts will bring us new hopes for cancer prevention and treatment.

Conflicts of interest

The authors declare no competing interests.

Supplementary Material

Acknowledgments

We thank the National Natural Science Foundation of China (82073729) for financial support.

Biographies

Biography

Tao Ye.

Tao Ye

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Tao Ye received his Bachelor's degree from Chaohu University in 2020. Currently, he is pursuing his M.S. degree at the School of Biological Science and Technology, University of Jinan. His research mainly focuses on the screening and mechanistic study of antitumor lead compounds from natural products.

Biography

Peipei Shan.

Peipei Shan

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Peipei Shan received her Ph.D. from the Institute of Biomedical Science, East China Normal University. She joined the Institute of Translational Medicine, Qingdao University, Qingdao, China, in October 2017. Currently, she is working on the mechanism of tumor pathogenesis and the discovery of new anti-tumor drugs.

Biography

Hua Zhang.

Hua Zhang

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Hua Zhang obtained his Ph.D. in Medicinal Chemistry from Shanghai Institute of Materia Medica (SIMM) and did his postdoctoral research at The University of Queensland. He continued his academic career at SIMM for another four years and then joined University of Jinan in 2015. He is now a full-time professor in Natural Products and Medicinal Chemistry at the School of Biological Science and Technology. In addition to carrying on his efforts in natural product biodiscovery, his group has also been involved in the rational design and synthesis of enzyme (e.g. PRMT and HDAC) inhibitors for cancer treatment in recent years.

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