Open access peer-reviewed chapter
In vitro studies with TOP1 inhibitors.
Abstract
Topoisomerase 1 is the main enzyme playing an important role in relaxing. The supercoiled DNA strands allow the replication fork to transcribe the DNA to RNA and finally control protein production in active and replicating cells. Blocking this essential machinery is a cornerstone mechanism in treating tumors, such as liver, breast, and metastatic colorectal carcinoma. Irinotecan is a topoisomerase inhibitor that blocks the replication ending in DNA break and tumor cell death. This chemotherapy has been successfully used in combination to overcome metastatic colorectal carcinoma. The topoisomerase-1 inhibitor makes a protein DNA complex stuck with the replicating fork creating a single DNA break, unlike topoisomerase-2, which is responsible for double DNA break. This inhibitor is exposed to drug resistance with complex machinery. Drug resistance can occur as a result of altered DNA methylation, changes in topoisomerase expression, histone recombination, or drug export pump. High expression of topoisomerase-1 is a marker of the number of tumors suggesting multiple roles of topoisomerase-1.
Keywords
- topoisomerase-1
- irinotecan
- colorectal carcinoma
- epigenetic
- drug resistance
- supercoiled DNA
1. Introduction
DNA topoisomerases are important enzymes that modify the double-stranded DNA topology. They act in both directions to relax supercoiled DNA and enforce relaxed DNA to be tenser. These 3D structure modifications share in the control of DNA transcription and finally protein translation. In humans, there are two types of isomerases: the first one is topoisomerase-1 (TOP-1); the second one is topoisomerase-2 (TOP-2). Because of the canonical functions of TOPs, these enzymes have been a target for treating overactive cells, such as cancer cells or bacteria that contain different types of isomerases [1]. TOPs covalently bind DNA and create DNA adducts aiming to release the over-twisted DNA strand. Topoisomerase inhibitors (TOP inhibitors) create TOP/DNA obstacles in front of the active replicating fork. The smash between the fork and the DNA protein complex ends in a DNA break. TOP-1 differs from TOP-2 in that the first one is responsible for a single DNA break, while the latter is involved in double DNA damage [2]. In this chapter, we are going to discuss the relationship between TOP-1 and cancer. The chapter aims to put a spot on the role of TOP-1 in cancer colon, and TOP-1 inhibitors’ role to overcome cancer colon. It is important to discuss TOP-1 resistance.
1.1 Topoisomerase-1 and cancer
Since 1989, scientists recorded the high expression of TOP-1 in aggressive tumors such as late-stage colorectal carcinoma. It seems that such tumors use TOP-1 to support their replication machine. These findings were reported in renal tumors or brain neoplasms. The excess TOP-1 activity was highest seen in leukemia besides cancer colon. Moreover, TOP-1 overactivity correlated with poor prognosis in these tumors [3, 4].
TOP-1 may exert complex relation to the process of carcinogenesis. Experimental work demonstrated that knock-out TOP-1 plays a role in oncogenic property. The knock-out cells showed less aging and more replication capacity. Interestingly, the genome was more resistant to DNA damage [5]. More recent work showed opposite results concluding that oxidative stress induces cell aging with excess TOP-1 activity [6]. It is suggested that both senescence and active replication are parts of the process of neoplasia. An immunohistochemical study of secondary pterygium showed both overexpression of TOP-1 and glutathione in the same pathology [7].
A recent study on cancer liver samples using both immunohistochemistry and microarray demonstrated upregulation of TOP-1 and TOP-2 expression in poor prognosis liver cancer candidates. Both genes were involved in the function of the guardian p53 pathway and apoptosis cascade. The study showed that it is a wise idea to consider topoisomerases as oncogenes. Furthermore, these 2 targets are potentially good potentials for cancer chemotherapy [8]. TOP-1 inhibitors include etoposide, camptothecin, and Adriamycin with wide use in clinical practice. More research on different extracts to decrease the side effects and improve the efficacy is going on [9, 10]. Studies in yeast demonstrated that active or aberrant TOP-1 induces DNA mutagenicity, and later on, unstable DNA contributes to cancer development. This mechanism is controlled in mammalians by safety SUMOylation post transcription mechanism [11]. The small ubiquitin-like modifier (SUMO) is a pathway that contributes to transcription, immunity, signaling, and stabilization of the genome. Unfortunately, defective TOP-1 and its regulatory SUMOlyation may end in tumor genesis [12].
Topoisomerase-1 gene expression is considered a marker of drug response in metastatic colorectal carcinoma. It is recommended to use irinotecan (TOP-1 inhibitor) to treat these advanced colorectal tumors where TOP-1 expression is over-expressed. It seems that these tumors over-express TOP-1 to support the tumor DNA repair making the tumor cell resistant to death [13]. TOP-1 inhibitor irinotecan has been tested on cell lines to induce acetylation of the p53 and interrupt the histone deacetylase activity, making the resistant genome of growing cancer cells suitable for DNA break. It seems that TOP-1 inhibition is challenging in the understanding of the cancer colon pathway [14]. Metabolomic analysis of colorectal carcinoma cells treated by irinotecan showed shifting to glycolysis and an increase in oxygen consumption as markers of good response to cancer chemotherapy [15].
1.2 Topoisomerase inhibitors
The TOP-1 inhibitors were first discovered from a tree growing in China named Camptotheca acuminate. The extraction product of this tree was a component of Chinese medicine. Later on, in the 70s and the 80s, research work managed to construct TOP-1 inhibitors in the lab and formulate them as chemotherapy [16].
Drugs inhibiting TOP-1 have been used for decades to treat malignant tumors. These chemotherapies are called TOP-1 poisons. The first-generation candidate of these compounds is camptothecin. Newer generations, include irinotecan, topotecan, and belotecan [17]. Like any chemotherapy, camptothecin derivatives have many side effects. Scientists are working with non-camptothecin generations with fewer hazards [18]. TOP-1 poisons have been prescribed for multiple tumors including colorectal cancer, ovarian tumors, small cell lung malignancy, and myeloid proliferative disorders [19]. Aggressive neoplasms over expressing TOP-1 are suggested to be good candidates for TOP-1 inhibitors as in breast or ovarian cancers besides colorectal malignancy. It is expected that TOP-1 will be radical chemotherapy for these tumors exposing their DNA to break [20, 21, 22]. The researchers were working with TOP-1 inhibitors for half a century. They managed to get the crystal structure of the enzyme. The advances in molecular docking in the last 20 years give scientists a great opportunity to design lots of derivatives to discover new drugs that are more potent with more specific functions aiming to reduce the side effects. However, the difficulty was that the mechanism of action is canonical that it is extremely difficult to avoid hazards. To overcome such obstacle, the advances in drug delivery will reduce the side effects by loading the chemotherapy dose directly onto tumor cells [23].
1.3 Topoisomerase-1 inhibitors and cancer colon
Irinotecan is considered the first drug of choice in treating metastatic colorectal carcinoma in combination with 5 fluorouracil and folinic acid. Irinotecan is a working TOP-1 inhibitor that is metabolized in the liver to a more active compound SN-38. This chemotherapy is characterized by a high volume of distribution. Fortunately, cancer cells have excess carboxylesterase enzymes that can metabolize irinotecan into its active component [24, 25, 26]. Irinotecan is a derivative of camptothecin and was approved for cancer colon in 1994. Its major side effects are neutropenia and diarrhea, which are responsible for dysbiosis. This chemotherapy was approved for children and adults. It is successful for metastatic colorectal neoplasia, as well as, solid tumors. The drug was constructed by the Japanese Yakult Honsha company. The newer generation products have been tested as new chemotherapy but failed in the late clinical phases such as rubitecan, gimatecan, lurtotecan, diflomotecan, elomotecan, silatecan, exatecan, namitecan [27, 28].
New compounds are being verified for TOP-1 inhibitors with better profiles. These compounds include belotecan and gimatecan. The first one is hydrophilic while the latter is dissolved in fat [29, 30].
Belotecan has been used to treat resistant ovarian tumors with better side effects in combination with other new modalities [31]. Other trials have been applied to treat lung carcinoma and biliary tumors [32, 33]. There is little data about the efficacy of belotecan on colorectal neoplasms. On the other hand, gimatecan showed promising results in brain tumors [34].
The advances in nanotechnology and drug delivery can overcome the side effects of traditional TOP-1. Nano liposomal irinotecan has been applied in a pancreatic neoplasm with the hope to achieve success. The results expressed better side effects, but the overall survival represented a weak response [35]. Nano liposomal irinotecan, in combination with other classic chemotherapy, showed better cancer pancreas response. Diarrhea seems to be less counted, but the patients still suffered from neutropenia in a fifth of cases treated to the new model [36].
In regard to colorectal cancer, there are promising clinical trials that liposomal TOP-1 will help in overcoming late-stage conditions. The experimental trials in mice showed better survival rates with fewer side effects [37]. Another strategy is to use a lipophilic active gradient of irinotecan SN38 to suppress advanced colorectal tumors. The results showed a successful modality and the FDA approved the drug for the treatment of late-stage cancer colon [38].
New drugs, which are non-camptothecin derivatives, have been introduced to manage different tumors. These modalities include dibenzonaphthyridines, as well as, indeno isoquinolines. They are more strong stable DNA-protein complexes. Trials of metals such as platinum, gold, copper, zinc, and others have been suggested as TOP-1 modulators [39].
More research work is concerned with indenoisoquinolines, regards the capability to inhibit TOP-1. These new groups of the drug are subjected to structural modification. They represent promising drugs with potentially fewer side effects. It is proposed that the new chemical will have a multi-mechanism of action like nuclear receptors targeting, TOP-2 interaction, modulating estrogen receptors, and manipulating VEGFR and HIF-1 alpha [40]. Studies suggested that indenoisoquinolines are weak TOP-1 inhibitors in combination with other functions. It seems that weak TOP-1 inhibitors in conjunction with other drugs, or even other pathways, are good rationales for modern cancer therapy [41].
1.3.1 Indenoisoquinolines
More than 20 years ago, a group of scientists managed to create a new anti-TOP-1 chemical 6,11-dimethyl-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one. This compounds the parent of quinolone family, and it exerted promising results on different human cell lines [42]. Since that time, dozens of derivatives have been introduced to be tested experimentally. These compounds have the advantage of being flat ones that strongly bind the TOP-1/DNA hybrid. The new compounds bind the TOP-1 at the arginine 364 of the enzyme TOP-1 [43]. These potential new drugs showed stronger cytotoxicity relative to their anti-TOP-1 mechanism and are expected with combined dynamic to have a less toxic profile [44]. Other pathways affected by indenoisoquinolines include induction of cell cycle arrest, stimulation of apoptotic response, and modulation of MAPK cascade. Other potential role includes phosphorylation of JUNK pathway and inhibition of the oncogene MYC pathway [45]. On the other hand, despite the strong multi-dynamic function of these drugs, they did not replace the classic TOP-1. Research is still going to tune drugs with a balance between efficacy and hazard effects.
1.4 Topoisomerase-1 inhibitor resistance
Topoisomerase inhibitors, like other chemotherapy, are subjected to resistance. Many mechanisms are involved in this process. The tumor uses efflux mechanisms to reduce the level of the drug in the tumor mass. Mutations of the TOP-1 make the drug less effective in inhibiting the enzyme. Other strategies include enhancing the DNA repair to overcome TOP-1 poison. The tumor cells stimulate p53 to support the malignant mass to survive and suppress apoptosis. Limiting the drug’s bioavailability can be another way to overcome chemotherapy [46].
Recent work put the spot on cancer colon stem cell role in the development of cancer. These highly replicating cells can overexpress the ATP cassette transporters. The experimental work showed that the over-expressed MYC oncogene supports the tumor resistance by enriching ATP transporters [47]. The ATP cassette sub-family G isoform 2 is expected to overcome xenobiotic effects with abundance in the GIT and near blood vessels. Besides their role in cancer stem cells, they represent a defense mechanism against chemotherapy. Tyrosine kinase inhibitors, phosphodiesterase-5 inhibitors, and the fumitremorgin-type indolyl diketopiperazine have been used to support chemotherapy to overcome resistance by inhibiting the ATP transporters [48]. The resistance was marked in cases associated with the marker ATP cassette type G group member 2 [49]. To overcome the resistance obstacles, the use of an ATP cassette inhibitor has been introduced. Another method was to apply the new TOP-1 inhibitor FL118, which possesses the capacity to overcome efflux resistance. This new analog is weakly transported by ATP carriers [50]. KO143 is a potent antagonist of ATP cassette sub-family G member 2. It is stable and not easily metabolized by the cytochrome enzymes in the liver [51].
ATP-binding transporters have been involved in the resistance to TOP-1 inhibitors in cancer breast. Experimental work on cancer colon cell lines concluded that colon tumor cells expressed a similar mechanism. Furthermore, it is possible to add compounds inhibiting efflux mechanisms such as SCO-201 to the chemotherapy regimen to sensitize the tumor to respond to the chemotherapy indicating better survival rates [52]. It is important to notice that overexpression of the ATP transporters is a marker of resistance to cancer colon. It is recorded that candidates’ higher expression is most likely to resist camptothecin derivatives.
1.4.1 ATP efflux mechanism
The master mechanism of resistance of colorectal tumors to chemotherapy is drug efflux mechanism. The ATP-binding cassette sub-family G member 2 (ABCG2) is responsible for decreasing anti-TOP-1 bioavailability inside the tumor microenvironment leading to failure of the therapy [53]. The promoter regulating the expression of these shuttles is epigenetically regulated by methylation. Aggressive tumors express high ATP cassettes to get rid of the xenobiotic load. Hypomethylation of the promotor-regulating ATP transporter was recorded in different tumor cell lines [54]. The ABCG2 is formed from a sequence of 655 amino acids weighing 72-kilo Dalton. The structure is homodimer with two nucleotide-binding sites to export the drugs [55, 56]. The transporters play important role in the maintenance of the tumor microenvironment. They keep the balance of osmotic pressure. They have another role in antigen processing and modulation of cell division. Cell trafficking and cholesterol metabolism are affected by the ATP transporters [57].
Recently, N6-methyladenosine (m6A) RNA modification has been a new modality to treat ATP transporter through epigenetic mechanism at the RNA level [58].
Another important mechanism to defeat chemotherapy is the mutation of DNA repair response. In cancer cells, positive mutations make the tumor resistant to TOP-1 effects. The tumor genes such as BRCA1, BRCA2, PLAB2, and BARD1 have been mutated. Studies recorded alterations in 86 genes related to DNA repair. Such overactivity makes the single DNA break to the TOP-1 less effective [59].
Cancer colon cells expressing both SENP-1 (sentrin specific protease) and HIF-1α (Hypoxia inducing factor alpha) are resistant to chemotherapy. Both of them overexpress proteins SUMO pathway and make the tumor resistant to hypoxia [60]. Recently, SENP1 is a target of new compounds to develop a new regimen to overcome resistance [61].
Cancer cells can develop an alternative way to resist chemotherapy, specially irinotecan by augmenting the detoxification pathway. The active metabolite SN-38 is inactivated by glucuronidation making the drug short of killing the cancer cells. The nuclear receptors pregnane X receptors and steroid/xenobiotic receptors enhance the metabolism process of SN-38. It is important to notice that they are expressed in excess in the liver and the GIT. They also induce a battery of genes that express xenobiotic transporters that make irinotecan ineffective within a short period [62].
To repel TOP-1 inhibitors, the tumor cells induce a high copy number of the TOP-1 gene to make the drug subtherapeutic to kill the neoplastic cells. Furthermore, the TOP-1 is subjected to chromosomal alterations to be transcribed from different loci. These overexpressed loci are considered biomarkers of the drug response later on [13, 63].
The cancer colon cells are smart enough to create mutated TOP-1 that is not responding to the classic inhibitors. Experimental studies on resistant cell lines demonstrated several mutations that resist camptothecin derivatives or the new generation TOP-1 drugs [64].
The antioxidant balance in the cancer metabolism plays important role in protecting the tumor cells from xenobiotic toxicity and oxidative stress. One of the common mechanisms to support the redox is to express a high amount of glutathione reductase allowing the tumor to grow in unnatural situations and protect the mass from chemotherapy [65].
Another model for TOP-1 inhibitor resistance is colorectal tumors expressing active epidermal growth factor (EGFR). It was recorded that the active metabolite SN-38 is subjected to resistance because of the over-expression of EGFR. This factor triggers a trophic response in cancer growth via a cascade of a signaling pathway [66, 67].
1.5 Epigenetic therapy and cancer colon
New work has applied epigenetic modifier agents in combination with classic chemotherapy with a promising response. The epigenetic changes improved the drug response and reduce the needed dose to improve the clinical outcome. These transformers include DNA methyl transferase, decitabine, azacytidine, and zebularine. The study also used drugs that were considered histone deacetylase inhibitors including the well-known mood stabilizer valproic acid with promising results [68]. During the process of cancer evolution, cancer cells have different strategies to survive. It was recorded that p53 is mutated and histone deacetylases (HDACs) are over-expressed. It was considered that this epigenetic mechanism corresponds to drug resistance. Experimental inhibition of HDACs by small hairpin RNAs resulted in a better response of chemotherapy against the resistant SW480 cell lines. Indeed, epigenetic modification is part of the process of carcinogenesis and drug resistance response [69].
The DNA topology is inherited by an epigenetic mechanism. However, the process is unclear. The status of DNA twisting is a unique criterion of each cell type. This information is considered a cellular memory that is transmitted from the parent cells to the daughters by mitosis. The status of DNA 3D structure controls transcription and gene expression [70]. It has been recorded that parent cells with excess supercoiling deliver daughter cells with the impaired cell cycle. DNA supercoiling is important in the process of chromatin condensation. Previously, it was thought that DNA remains quiet during the process of mitosis. However, recent evidence that a battery of genes is still active in the mitosis process to be involved in the development of the next generation of cells [71]. The activity of the TOP-1 allows the chromatin to adapt to the DNA-positive supercoils. On the other hand, an excess of negative supercoils ends in DNA/RNA hybrid structure with resulting in DNA damage [72]. Although, DNA/RNA hybrid is considered a mechanism of regulating gene expression called an R loop [73].
1.6 Topoisomerase-1 biomarkers of response
The first line of treatment for wild-type RAS metastatic colon cancer was the anti-EGFR immunotherapy cetuximab or panitumumab [74]. Experimentation searched for the colorectal cancer biomarkers in the blood. Recently, kits to extract the tumor cDNA are available clinically to evaluate associated parameters predicting the response of the tumor to classic chemotherapy. Moreover, liquid samples assaying RAS and BRAF oncogenes have a role in chemotherapy of colorectal cancer. The assays showed that tumors with wild-type RAS and BRAF were more responsive to camptothecin chemotherapy in combination with immunotherapy as a third line of treatment for colorectal metastasis [75]. The selection of the biomarkers as a strategy of personalized medicine in colon tumors reduces the side effects for precisely predicted response to the combined TOP-1 chemotherapy-related regimen. These markers include
1.7 Topoisomerase and other diseases
TOP-1 is an essential enzyme in the machinery of DNA transcription by modifying the topology of the DNA helix, and it is an important factor in stabilizing the genome. Furthermore, this enzyme has another role in the process of transcription in a way not directly related to unwinding DNA. Researchers proposed TOP-1 targets as a potential treatment for autism [78]. Mitochondria depend on the imported TOP-1 to relax the DNA during the process of transcription. Mitochondrial DNA damage is involved in many, such as neurodegenerative disorders and cancer. TOP-1 with its double role is a valuable object of cancer chemotherapy [79].
Another important scope of drugs inhibiting TOP-1 is modulating the immune response on exposure to microorganisms. Experimental studies showed that loading mice with endotoxins expressed a less harmful immune reaction than candidates tested with TOP-1 inhibitors. Low-dose TOP-1 chemotherapy such as camptothecin improved the antiviral unfavorable reaction. Interestingly, the low-dose poison with mild DNA break improved the situation in fighting the viral load [80].
Recently during the COVID-19 crisis, topotecan (TOP-1) has been applied to reduce the aberrant immune response to corona infection. Experimental work on hamsters and mice showed that a topotecan dosing improved the immune response. The TOP-1 inhibitors may exert antiviral capacity [81].
1.7.1 Mutated TOP-1
Mutated TOP-1 was a part of different chronic disorders. Malfunctioning TOP-1 is associated with unstable DNA. The causes of such complex pathology are still unknown. The hybrid TOP-1/DNA abnormal complex works as a TOP-1 inhibitor ending in excess DNA break. These phenomena were recorded in massive spinocerebellar disorders. It was reported that ATM (ataxia telangiectasia, mutated), a serine/threonine protein kinase, plays an essential role in cell cycle activation, chromatin remodeling, DNA repair, or stimulation of apoptosis. Experimental knockout of ATM showed accumulated pathogenic TOP-1/DNA complex with excess DNA break creating neurodegenerative pathology in animal models. Furthermore, healthy ATM can mediate TOP-1 complex ubiquitination [82]. These results established the idea that healthy TOP-1 is essential for development of central nervous system.
1.8 Innovations and novel strategies from a clinical perspective
Recently, the advances in multi-omic studies provided a signature of metastatic colorectal carcinoma cases aiming to predict the response of the chemotherapy. Metastatic candidates expressed unique proteomic profiles. There is a distinct profile for colorectal tumors, associated with liver metastasis. As regarding the genomic profile, there was no significant difference between early or late-stage tumors. These findings build up personalized strategies to treat or predict poor prognosis. Metastatic colorectal patients showed overexpression of oxidative phosphorylation and Krebs cycle enzymes [58]. A new strategy to use drugs that inhibit the rate of metabolism has been introduced in clinical trials as an adjuvant in colorectal metastasis in the liver. This modality is considered as tumor micro immunity reprogramming [83].
On the other hand, the analysis of circulating tumor DNA in the blood showed a mutation signature related to the tumor outcome. The status of RAS/BRAF mutations correlated with the prognosis of patients. The RAS/BRAF mutation load correlated with overall survival. As fewer mutations were detected in the blood sample, higher rates of remission were detected [84]. Another clinical study showed a similar profile. Excessive mutation RAS/BRAF suggested poor response to the first line of treatment of colorectal carcinoma [85].
A new modality mXELIRI (capecitabine plus irinotecan) has been recently applied with or without immunotherapy. The patients tolerated therapy for colorectal tumors with acceptable efficacy and toxicity profile [86]. Other trials have been applied to combine irinotecan and vincristine in soft tissue tumors [87].
New combination chemotherapy has been introduced recently. The anti-HER3 antibody patritumab has been added to the new TOP-1 inhibitor DX-8951 derivative (DXd) to treat resistant colorectal cancer with potential success [88].
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2. Conclusions
TOP-1 gene and TOP-1 target protein are important in both carcinogenesis and pharmacology of different tumors. It is concluded that TOP-1 classic inhibitors Table 1 are the main line of treatment of metastatic colorectal carcinoma. These drugs with complex mechanism of action are associated with profound side effects and subjected to different types of machinery of drug resistance. The discovery of new drugs with multi dynamics, including mild TOP-1 in conjunction with other actions, is a promising modality to bypass the toxic effects of classic TOP-1 inhibitors as shown in Table 2. Too strong anti-TOP is no longer a wise strategy to apply because of the canonical TOP function in almost every cell. Epigenetic tools can be added to improve the chemotherapy outcome.
| Drug | The study | Cell line | Reference |
|---|---|---|---|
| Hydroxycampthecin | The drug inhibit TGF-beta1 and inhibit fibrosis | Human fibroblast | [89] |
| Homocamptothecin E-beta ring hydroxylactone | New anti TOP1 | Molecular docing | [90] |
| 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one | New anti TOP1 Managed to treat leishmania with good cytoxicity profile | Leishmania | [91] |
| 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives | Non campthecin TOP1 inhibitor | Human cancer cell lines (A549 and MCF-7) and in silico | [92] |
| 9-Aminocamptothecin (9-AC) | Anti TOP1 for prostate cancer with promising results | Prostate cell lines | [93] |
| Metallated porphyrins | Ant TOP1 for different cell lines | K562, U937, HL-60, Jurkat, A549 and HeLa cancer cell lines | [94] |
| Heteroliptic cupper | Anti TOP for mulriple cancer cell lines with success | Human lung (A549), cervical (HeLa) and colon (HCT-15) | [95] |
| Irintotecan | Alter metabolism of gut | Enterocytes | [96] |
Table 1.
| The drug | The study | The host | Reference |
|---|---|---|---|
| Exatecan derivative (DX-8951 derivative, DXd) | The drug was combined with the immunotherapy DS-8201a is a human epidermal growth factor receptor 2 (HER2) | HER2-positive NCI-N87 cells and HER2-negative MDA-MB-468-Luc cells incubated in mice | [97] |
| Topotecan (TPT) | Potential role in COVID patients with success in reducing the immune storm | Transgenic mice | [81] |
| Marine alkaloid lamellarin D drivatives | More effective in treating cancer colon | Murine colon cancer | [98] |
| AZD2014 or INK128 in combination with irinotecan | Induce apoptosis in Malignant peripheral nerve sheath tumors | Zebra fish | [99] |
| 7-Ethyl-10-hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT-11) | Liver breast and colon cancer model expressed better response | Both in vivo and in vitro | [100] |
| Quercetin | A flavonoid with anti TOP anti-gastric cancer | Both in vivo/in vitro | [101] |
Table 2.
In vivo studies with TOP1 inhibitor.
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