A REVIEW ON TAXANES: AN IMPORTANT GROUP OF ANTICANCER COMPOUND OBTAINED FROM TAXUS SPHTML Full Text
A REVIEW ON TAXANES: AN IMPORTANT GROUP OF ANTICANCER COMPOUND OBTAINED FROM TAXUS SP
Department of Botany, Government General Degree College, Mohanpur, Paschim Medinipur - 721436, West Bengal, India.
ABSTRACT: Taxol is an important drug used for the treatment of various types of cancer. It is primarily obtained from Taxus brevifolia bark and has a long history of the developmental program of 50 years. It functions as a microtubule-stabilizing compound and inhibits mitosis of cancer cells, thereby providing a protective role in the treatment of cancers. In addition to it, taxol also interferes with a number of biochemical pathways and protein to bring about apoptosis and cell death. Since its inception, taxol has undergone various levels of modifications and formulations with a motive of making its action more effective. This has led to the development of Paclitaxel by Bristol-Myers Squibb for large scale commercialization. Consequently other semi-synthetic variants such as Docetaxel and Cabazitaxel were also developed for better actions. All these compounds are collectively called as Taxanes and contain a common ringed baccatin III structure in its molecule. This review is an attempt to illustrate the gradual development of anticancer taxanes from its precursor Taxol and its various pharmacological activities against the treatment of cancer. An extensive literature survey has been made to compile all the relevant information in relation to its development and pharmacological activity. Taxanes can be very well utilized in the treatment of various types of cancers. More clinical trials are a requirement of time for effective refinement of taxanes for the benefit of cancer patients.
Taxol, Taxane, Paclitaxel, Docetaxel, Cabazitaxel, Taxus brevifolia
From Nature to Laboratory: Taxol (generic name paclitaxel) is a microtubule-stabilizing drug used for the treatment of breast, ovarian, and lung cancer and is approved by food and drug administration, United States of America in the year 1992 1.
Chemically, taxol is a diterpenoid of natural product origin 2. Its history dates back to six decades when an extensive search for an anticancer drug was done by the National Cancer Institute (NCI) and the United States Department of Agriculture (USDA) between the year 1960 and 1981 through a screening program involving collection and testing of 115000 extracts from 15000 plants 3.
It was in the year 1962, USDA botanist Arthur S. Barclay and 3 other college student field assistants collected 650 plant samples from California, Washington, and Oregon, including bark, twigs, leaves, and fruit of Taxus brevifolia from Washington 4. In 1964, the samples, in the form of crude extracts having cytotoxicity, were then transferred to Monroe Wall at the Research Triangle Institute, and crystalline substances were first isolated in the Wall’s laboratory in 1966 with a proposed molecular formula containing carbon, hydrogen, oxygen. The name Taxol was first proposed to the crystals isolated from active extracts of Taxus brevifolia bark by Monroe Wall 5.
The accomplishment of the program was brought about through the decipherence of the chemical structure of taxol from Taxus brevifolia by the research group of Wani, Wall and coworkers in the year 1970 under a contract of Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, United States of America 6. Taxol was then passed to NCI for further analysis and development of the drug. A further investigation of the pharma-cological activity of Paclitaxel was done by various groups of researchers. Fuchs and Johnson, 1978, reported taxol as an antineoplastic agent acting as mitotic spindle poison 7. Later, Drs Schiff, Horwitz, and coworkers in 1979 investigated and verified the potent cytotoxic properties of Paclitaxel on the growth of human cervical cancer cells (HeLa) and also its ability to block cell division in late G2 or M phase of cell cycle 8, 9.
By the year 1984, further investigation on the biological activity of taxol and taxol acetates was performed 10, 11. The phase I clinical trial of taxol was first performed in the year 1984, while the phase II trial was initiated in 1985 12, and in the year 1987, Wienrik reported a phase I trial and pharmacokinetic study of taxol 13. Taxol was found to possess the cytotoxic potential of clinical significance when a study on ovarian cancer reported that 30% of the patients suffering from platinum-resistant ovarian cancer responded partially or completely 14. The report on the phase II trial of taxol on metastatic breast cancer was done by Holmes and coworkers in the year 1991 15. The high demand for taxol resulted in severe depletion of the population of Taxus brevifolia as removal of barks resulted in the death of the trees. Thus, in 1992, the Pacific Yew act was passed to safeguard the tree from further population depletion. The act ensured that federal lands would be managed for sustainable harvesting and long term conservation of pacific yew 16. Consequently, in order to obtain large quantities of taxol, NCI decided to transfer taxol to Bristol-Myers Squibb (BMS) for commercialization, which then trademarked the name ‘taxol’ and proposed a new generic name ‘Paclitaxel’ in the year 1992 17.
Paclitaxel, originally extracted as taxol from the pacific yew, Taxus brevifolia barks, exhibited a low yield through a destructive method of extraction and complicated way of purification 18. In addition to it, further development of drugs faced an initial hiccup due to its insolubility in water. The compound was slightly soluble in octanol, propylene glycol, butanol, and freely soluble in dimethyl acrylamide. The final formulation was achieved by Bristol-Myres Squibb using 50% Cremophor ELTM (CrEL) and 50% dehydrated ethanol as solvent. The final formulation contained 30 mg of Paclitaxel in 5 ml of 1:1 (v/v) of the mixture 19. CrEL is a surfactant-containing formulation vehicle used for a number of drugs having poor water solubility including Paclitaxel 20.
In order to overcome the low yield issue, in the year 1995, Sanofi-Aventis, Bridgewater, NJ developed Docetaxel (Taxotere®), a semi-synthetic analog of Paclitaxel whose active ingredient is docetaxel, a lipophilic compound also having low water solubility but solubilized by micelle formation using polysorbate 80 21. Docetaxel differs from paclitaxel at two positions in its molecular structure, which enhances its solubility in water 22. In June 2010, Food and Drug Administration, United States approved a new taxane by the name Cabazitaxel (Jevtana ®) as an alternative drug to the patients suffering from castration-resistant prostate cancer (CRPC) 23. It is a semi-synthetic microtubule inhibitor and induces cell death by stabilization of microtubules 24. Since its affinity towards P-glycoprotein is poor, the chances of resistance are also minimized, making it more effective 25.
Since its inception, a number of other semi-synthetic variants of taxol have been produced by pharmaceutical companies. These diterpenoids, including paclitaxel, docetaxel, and cabazitaxel, extensively used as chemotherapeutic agents for the treatment of cancer, are collectively called taxane 26. In this article, the term taxane would henceforth be used to designate taxol and associated compounds having anticancer activity. The important events associated with the development of Taxol in tabulated in Fig. 1.
FIG. 1: IMPORTANT EVENTS ASSOCIATED WITH THE DEVELOPMENT OF TAXOL
Taxus as Source of Taxanes: Investigation and isolation of taxanes and related compounds have always been a matter of curiosity since the last 6 decades. Structural elaboration of taxine, taxinine and O-cinnamoyl taxicin-I occurring in Taxus baccata L. were done way back in 1963 27, 28. Consequently taxol (Generic name paclitaxel) was first isolated from Taxus brevifolia in the early 1970s 29. Taxol is produced by all species of Taxus though the taxoid content may vary from species to species and also between tissues of same species though the taxane biosynthetic pathway is the same for all the species 30. An important breakthrough was the discovery of 10-deacetylbaccatin III, which later provided the precursor for semi-synthetic production of taxol 31, 32.
The environmental factors controlling the production of taxol have also been explored by various groups of researchers. It was found that there was a seasonal variation in taxol content in shoots and barks of Taxus brevifolia with variations more marked in barks in comparison to shoots 33. It was also reported that the taxol content was higher in barks as compared to foliage through its content increases with age in both the plant parts 34. The monthly variations of taxol content were also noted in Taxus baccata var. fastigata. It was observed that the highest taxol content was in the month of April.
The plants with green leaves contained more taxol in comparison to the plants with golden leaves 35. Nine compounds, namely paclitaxel, pentaacetoxy-taxadiene, 1β-hydroxybaccatin I, baccatin IV, baccatin III, taxusin, C-14 oxygenated taxoid, rearranged taxoid and 7-xyloxyl-10-deacetyltaxol C was isolated from the roots of Taxus wallichiana 36. In Taxus brevifolia, it was found that the concentration of taxanes decreased from the base of the stem to the tip of the plant which is due to the presence of higher taxane concentration in the phloem tissues and thickness of the inner bark from base of the stem to tip of the branch. The seasonal variation in taxane concentration was also observed, which had an increasing trend from late spring to early summer, indicating the ideal time to harvest these natural products and metabolites 37.
The regional variation of taxane concentration was also observed in the barks and needles of Taxus cuspidata, also indicating the renewable scope of harvesting raw material for mass production of drugs 38. The variation in taxol content in the seeds of Taxus cuspidata reveals that the content is highest in testa followed by endosperm and embryo respectively. The taxol content of the fresh seed reached its maximum in the middle stage of seed maturation and declined with further maturity 39.
Chemical Nature of Taxanes: Taxanes are a group of structurally similar compounds that possess a common core ring structure called baccatin III. The taxanes are composed of a four-member oxetan ring attached at C4-C5 position and an ester side chain attached at C13. The configuration of the ester chain is important for the antitumor property of taxanes. The configuration differs from that of Paclitaxel in two ways, namely (i) in the mode of attachment to the C59 carbonyl in the C-13 side chain and (ii) absence of acetyl group esteriﬁed to the C-10 hydroxyl of the baccatin ring 40. The third generation semi-synthetic analog of docetaxel is cabazitaxel. The molecular structure of docetaxel and cabazitaxel are almost similar and varies only in the presence of 2-methoxy side chains in cabazitaxel that substitute hydroxyl groups in docetaxel 41. The structures of Baccatin III, paclitaxel, docetaxel, and cabazitaxel molecules are depicted in Fig. 2, 3, 4, and 5, respectively.
Anticancer Activity and Mode of Action of Taxanes:
Anticancer Activity: Taxanes are being used in the cure of a number of cancers. At present, they are also used in conjugation with some other drugs in order to increase their activity and effectiveness.
Various formulations of taxanes, including micelles and nanoparticles, are also used to enhance the activity of the drug. The pharmacological activities of taxanes against selected cancers illustrated as follows.
Liver Cancer: Hepatocellular carcinoma or liver cancer is the 6th commonly diagnosed cancer and 4th leading cause of death in the year 2018, with 80% of the case reported from sub-Saharan Africa and eastern Asia 42.
It has been reported that nearly 692000 cases of hepatocellular carcinoma are reported per year, which amounts to 7% of all cancer deaths worldwide 43. Hepatitis B virus (HBV) or hepatitis C virus (HCV), alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD) are the most common risk factors of hepatocellular carcinoma 44. The pharmacological activities of taxanes in counteracting liver cancer is presented in Table 1.
TABLE 1: PHARMACOLOGICAL ACTIVITY OF TAXANES AGAINST LIVER CANCER
|Taxane type||Study system||Important outcome of study|
|Paclitaxel loaded in nanostructured lipidic carriers||In-vitro: HepG2 liver carcinoma cells
In-vivo: Wistar rats
|In-vitro: Dose-dependent decrease in cell viability and enhancement of ROS generation. Initiation of chromatin condensation, presence of condensed and fragmented nuclei indicative of apoptosis.
In-vivo: Enhanced absorption of Paclitaxel 45.
|Docetaxel in Gold nanoparticles encapsulated
|In-vitro: HepG2 liver carcinoma cells
|In-vitro: Concentration-dependent decrease in cell viability by Docetaxel .nanoparticles. Conglomeration of cells, development of blebs and bulge indicating the onset of apoptosis.
In-vivo: Restoration of normal liver architecture in mice treated with docetaxel nanoparticles 46.
|Docetaxel carboxymethyl cellulose nanoparticles||In-vitro: Hepatic stellate cells, Hep3B,HLF Human carcinoma cells
In-vivo: Male C3H/HeNCrNarl mice
|In-vitro: Dose-dependent decrease in the percentage of cell viability of hepatic stellate cells, HCA-1, Hep3B, and HLF cells.
Molecular level: Dose-dependent downregulation of α- smooth muscle actin (α-SMA). and collagen I in hepatic satellite cells (HSCs) at both protein and mRNA levels
In-vivo: Inhibition of tumour growth 47.
|Cabazitaxel||In-vitro: SK-hep-1, SM- MC7721, Huh-7, HCC-LM3, Huh-TS-48, and SK- sora-5||In-vitro: A time and dose-dependent inhibition of Sk-hep-1, Huh-7, SMMc-7721, Huh-7, and HCC-Lm3 cell lines.
Cell cycle arrest: Significant increase in cells at G2-M phase upon treatment with cabazitaxel in SK-hep-1 and Huh-7 cell lines.
Molecular-level: Decrease in expression of Cdc25c, Cdc2, pCdc2 and cyclin B1 protein levels.
Induction of apoptosis: Increase in the ration of apoptotic cells in case of SK-hep-1 and Huh- 7 cells along with a decline in anti-apoptotic protein Bcl2 and a stronger cleavage of poly ADP-ribose polymerase (PARP) 48.
Lung Cancer: Lung cancer is the most common malignancy and cause of cancer deaths worldwide in past few decades49.The deaths due to lung cancer is expected to reach 3 million by the year 2035, with the incidence rate likely to double in both men (from 1.1 million in 2012 to 2.1 million in 2035) and women (from 0.5 million in 2012 to 0.9 million in 2035) 50. The occurrence of lung cancer is higher in developed countries than in less developed countries and is related to tobacco smoking 51. The pharmacological activities of taxanes in counter-acting liver cancer are presented in Table 2.
TABLE 2: PHARMACOLOGICAL ACTIVITY OF TAXANES AGAINST LUNG CANCER
|Taxane type||Study system||Important outcome of study|
|Paclitaxel and survinin siRNA encapsulated into polyethyleneimine-block-polylactic acid||In-vitro: A549, A549Luc lung cancer cells.
Animal Model: BALB/c nude mice
|In-vitro: Increase in cytotoxicity, nuclear fragmentation, chromosome abnormality and induction of G2/M cell cycle arrest in A549 cells.
In-vivo: Effective tumor inhibition 52.
|Caffeic acid with Paclitaxel||In-vitro: Non-small cell lung cancer (NSCLC) H1299 cells and normal Bease-2b cells
|Antiproliferative action: Decrease in proliferation of NSCLC H1299. Arrest of H1299 cells is sub G1 phase of cell cycle and induction of apoptosis.
Molecular level: activation of Bax, Bid, and downstream cleaved PARP, and phosphorylation of extracellular signal regulated kinase1/2 and c-Jun NH2-terminal protein kinase1/2. Activation of MAPK pathway involved in apoptosis53.
|Paclitaxel (PTX) loaded micelle delivery system (TP-M) with vitamin E-TPGS (TPGS) and PlasdoneS-630 Copovidone (PVPS630) as carriers||In-vitro:Caco-2, A549 and Lewis lung cancer cells
In-vivo: Male Sprague-Dawley rats and male C57BL/6 mice
|In-vitro: PTX-TP-M exhibited higher toxicity to A549 and Lewis cells than PTX alone due to improved cellular uptake.
In-vivo: The tumour growth inhibition was higher upon treatment with PTX-TP-M. Reduction in tumour cell volume and mitotic cells 54.
|Docetaxel loaded PEGylated liposomes with telimisartan||In-vitro: A549 lung cancer cell.
In-vivo: Sprague–Dawley rats, athymic Nu/nu mice
|In-vivo: Significant inhibition of tumour growth and mostly intact lung integrity in mice co-treated with docetaxel and telmisartan.
Molecular level: Decrease in expression of antiapoptotic marker survinin and down regulation in expression of metastasis marker MMP9 and MMP2 in docetaxel and telmisartan cotreated groups 55.
Prostate Cancer: Prostate cancer stands second with respect to frequency of occurrence (after lung cancer) among men accounting 1276106 new cases and 358989 (3.8% of all deaths caused by cancer in men) deaths in 2018 56. The incidence of prostate cancer is highest in Oceania, followed by Northern America, Western Europe, Northern Europe, and the Caribbean, while African countries have lower incidence rates and mortality than developed countries 57. The major risk factors associated with prostate cancer are high Body Mass Index (BMI), smoking habit, consumption of processed red meat, animal fat/saturated fat 58. Table 3 illustrates the pharmacological activity of taxanes in counteracting prostate cancers.
TABLE 3: PHARMACOLOGICAL ACTIVITY OF TAXANES AGAINST PROSTATE CANCER
|Taxane type||Study system||Important outcome of study|
|Noscapine and Paclitaxel||In-vitro: LNCaP and PC-3 prostate cancer cell||In-vitro: Decrease in percentage of cell viability and increase in apoptosis in cancer cell lines
Molecular-level: Significant decrease in the mRNA expression of Bcl-2 and increase in the mRNA expression of Bcl-2-associated X protein Bax, and Bax/Bcl-2 ratio in LNCaP and PC-3 cells. Decrease in expression of androgen receptor and prostate specific antigen 59.
|Docetaxel with Desmopress in||In-vitro: PC3 prostate cancer cell
|In-vivo: Significant reduction in tumour volume in mice 60.|
|Docetaxel in combination with Impressic Acid and Acankoreanogenin||In-vitro: VCaP prostate cancer cell||In-vitro: Promotion of apoptosis in VCaP cells when treated with a combination of Docetaxel and Impressic Acid or Acankoreanogenin suggesting strong antiproliferative activity.
Molecular level: Reduced activity of Nuclear factor-κB (NF-κB). Decreased expression of Bcl-2, NF-κB, p-Akt, and phosphorylated signal transducer and activator of transcription 3(p-Stat 3) and increased expression of phosphorylated c-Jun N-terminal kinase (p-JNK) 61.
|Docetaxel-loaded nanoparticles||In-vitro: LnCaP and PC3 prostate cancer cells||In-vitro: A concentration dependent increase in cell death upon treatment with docetaxel loaded nanoparticles as evident from increase in lactate dehydrogenase release in the culture medium of in LnCaP , PC3 prostate cancer cells 62.|
|Cabazitaxel||In-vitro: Human prostate cancer LNCaP and PC-3 cells||In-vitro: Significant attenuation of proliferation of both the cancer cell lines.
Molecular Level: Reduction in levels of androgen receptor and androgen receptor-associated factors HSP90α, HSP40, and HSP70/HSP90 organizing protein.Suppression of activity of anti-apoptotic factor HSP60 63.
|Cabazitaxel and Silbinin co-encapsulated cationic liposomes||In-vitro: PC-3 and DU-145 prostate cancer cells||In-vitro: Dose-dependent inhibition of cell growth, inhibition of cell migration and induction of apoptosis upon treatment with cabazitaxel and silbinin loaded nanoparticles.
Cell cycle arrest: Colony formation and G2/M cell cycle arrest upon treatment with nanoparticles.
Nucleus morphology: Onset of apoptosis as evident from cell membrane shrinkage, membrane blebbing, nuclear granulation etc. 64
|Bone targeted cabazitaxel nanoparticles.||In-vitro: PC-3 and C4-2B-luciferase prostate cancer cells||In-vitro: A dose and concentration-dependent inhibition on percentage survival of PC-3 and C4-2B prostate cancer cells along with high affinity to bind with bones.
In-vivo: Significant reduction in tumor weight along with protection from bone lesion 65.
Pancreatic Cancer: Pancreatic cancer is the 11th most common cancer in the world, with 458,918 new cases resulting in 432,242 deaths (4.5% of all deaths caused by cancer) in 2018 66 with a five-year relative survival rate of 8% only 67. Pancreatic cancer is more common in males than in females and among black than among white 68. Hereditary unmodifiable factors are major risks of pancreatic cancer. Table 4 illustrates the pharmacological activity of taxanes in counteracting pancreatic cancers.
TABLE 4: PHARMACOLOGICAL ACTIVITY OF TAXANES AGAINST PANCREATIC CANCER
|Taxane type||Study system||Important outcome of study|
|Albumin bound Paclitaxel nanoparticles (nab-PTX) and S-nitrosated human serum albumin dimer (SNO-HSA Dimer)||Human Pancreatic cancer cell (SUIT2-GLuc)||Antitumour activity in SUIT2 cancer model: Effective suppression of ascites and distant metastasis along with best survival rate by combination therapy 69.|
|Docetaxel nanoparticles in combination with radiotherapy||In-vitro: AsPC-1, BxPC-3 pancreatic cancer cells
|In-vitro: Decrease in number of cell colonies, increase in apoptosis and degree of tubulin polymerization upon treatment with docetaxel in combination with radiotherapy.
Molecular-level: Increase in expression of caspase 3
In-vivo: Inhibition of growth in AsPC-1, BxPC-3 derived tumours70.
Breast Cancer: Breast cancer forms the most common cancer in women and ranks the second most common cancer across the world, with a projected 1.7 million new cases by the year 2020. 71 Inherited mutations in Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2) genes accounts to about 5-10% of breast cancers 72. It is reported that menopausal women are more prone to breast cancers than younger women under 45 years of age 73. Taxanes find extensive use in the treatment of breast cancers. The pharmacological activity of three taxane representative, namely Paclitaxel, Docetaxel, and Cabazitaxel in counteracting breast cancers, are illustrated in Table 5, 6, and 7, respectively.
TABLE 5: PHARMACOLOGICAL ACTIVITY OF PACLITAXEL AGAINST BREAST CANCER
|Taxane type||Study system||Important outcome of study|
|Paclitaxel in combination with sorafenib and radiation therapy||In-vitro: MDA-MB-231 breast cancer cells
In-vivo: BALB/c nude mice
|In-vitro: Dose-dependent Suppression in the proliferation of breast cancer cells with increased sub-G0-G1 phase.
Molecular-level: Increased expression of p21, CHOP, BAX, Apaf-1, and cleaved-caspase 3 and reduction in (B-Cell lymphoma) Bcl-2 levels suggesting induction of cell cycle arrest via caspase cleavage and inhibition of the Bcl-2 pathway.
Cellular level: Increase in levels of cytochrome C in the cytosol indicating apoptosis through a cytochrome c–dependent pathway.
In-vivo: Suppression of Caki1 and MB-231 cell xenograft tumors 74
|Cell-penetrating peptide producing nanoliposomes containing Paclitaxel||In-vitro: Human breast cancer cell MCF7.
In-vivo: BALB/c nude mice
|In-vitro cytotoxic effect: Inhibition of cell proliferation in concentration-dependent manner.
In-vivo antitumor efficacy: Significant tumor inhibition in MCF7 tumor bearing mouse model as evident from the reduction in tumor weight 75.
|Anti-EGFR anchored immunonanoparticle bearing Paclitaxel||In-vitro: MDA-MB-468 breast cancer cell.
In-vivo: Athymic mice
|In-vitro cytotoxic effect: Reduction in cancer cell viability
In-vivo antitumor efficacy: Tumour reduction and higher Paclitaxel accumulation in tumor plasma76.
|Nab-Paclitaxel with Azetolizumab.||Phase III trial: Human females||Results: Nab-Paclitaxel with Atezolizumab prolonged the progression-free survival in patients suffering from triple-negative breast cancer 77.|
|Paclitaxel and Gebcitabine through methoxy poly (ethylene glycol)–poly (lactide-coglycolide)-polypeptide nanoparticles.||In-vitro: 4T1, MCF-7and MDA MB-231 breast cancer cells||In-vitro: Inhibition of proliferation of 4T1, MCF-7, and MDAMB-231 in a dose-dependent manner by Paclitaxel. A combination of Paclitaxel with Gebcitabine resulted in a significant reduction in viability of 4T1, MCF-7, and MDAMB-231 below 50%, indicating a synergistic effect. Reversal of drug resistance of human breast cancer cell 78.|
|Paclitaxel loaded with keratin nanoparticles||In-vitro: MCF7, MDA MB 231 breast cancer cells||Cell Death: Significant increase in the percentage of late apoptotic cells in MCF-7 and early apoptotic cell MDA MB 231 after 48 and 24 hours of treatment respectively.
Molecular Level: Increase in expression of proapoptotic BAX gene and of cleaved caspase 3 (CC3) protein79.
TABLE 6: PHARMACOLOGICAL ACTIVITY OF DOCETAXEL AGAINST BREAST CANCER
|Taxane type||Study system||Important outcome of study|
|Docetaxel loaded in folic acid- and thiol-decorated chitosan nanoparticles||In-vitro: MDA-MBB-231 breast cancer cell||In-vitro: Improved cytotoxicity of docetaxel loaded in nanoparticles as compared to docetaxel.
Ex-vivo: Successful transportation and improved oral bioavailability 80.
|Dehydroartemisinin and docetaxel in pH sensitive nanoparticles||In-vitro: 4T1 mammary carcinoma cell||In-vitro: Reduction in cell viability along with G2/M cell cycle arrest
Molecular-level: Increase in expression of E-Cadherin and decrease in expression of p-AKT, NF-κB, p65 and Matrix metalloproteinase-2 (MMP-2) arrest 81.
|Docetaxel with ionizing radiation||In-vitro: MCF-7 breast cancer cell||In-vitro: A concentration and time-dependent decrease in viability of cancer cells upon co-treatment of docetaxel and ionizing radiation suggesting a synergistic effect82.|
|Docetaxel with SC-43
|In-vitro: MDA-MB-231, MDA-MB-468, and HCC-1937 breast cancer cells
In-vivo: NCr athymic nude mice
|In-vitro: Dose-dependent increase in anti-proliferative activity and apoptotic activity upon treatment with docetaxel and SC-43.
Molecular level: Decrease in expression levels of p-stat 3 and stat 3 downstream effector cyclin D1. Increased in an expression of SHP1 with a sequential combination of docetaxel and SC-43.
In-vivo: Suppression of tumor growth and tumor weight by combination treatment as compared to control 83.
|Noscapine and Docetaxel||In-vitro: MDA-MBA231 and MDA-MB-468 breast cancer cells
|In-vitro: Increased cytotoxicity and decrease in cell viability upon treatment with a combination of Noscapine and Docetaxel
Molecular-level: Downregulation in the expression of bcl-2, survivin, α-tubulin and pAKT.
In-vivo: Reduction in tumor collage levels and higher intratumoral .uptake of liposomes loaded with drugs 84.
|Ritonavir and Docetaxel||In-vivo: Cyp3a knockout mice (Cyp3a−/−)
Tumour model: K14cre; Brca1F/F; p53F/F mouse model
|In-vivo: Docetaxel and retanovir cotreatment resulted in a reduction of to one-third of its initial volume.
Histological observation: Significant pleomorphism along with expanded stroma, fibrotic changes and abundance of apoptotic cell and absence of necrosis in mammary tumor cells 85.
TABLE 7: PHARMACOLOGICAL ACTIVITY OF DOCETAXEL AGAINST BREAST CANCER
|Taxane type||Study system||Important outcome of study|
|Cabazitaxel-loaded Poly (2-ethylbutyl cyanoacrylate) nanoparticles||In-vitro: MDA-MB-231, MDA-MB-468, MCF-7 breast cancer cells.
|In-vitro: Toxicity of cabazitaxel to MDA-MB-231, MDA-MB-468, and MCF-7 breast cancer cell lines.
Inhibition of tumor growth: Inhibition of tumor growth and complete remission of tumors in mice upon treatment with cabazitaxel nanoparticles. Inhibition of expression of CD206, a marker of M2 macrophages (protumorigenic and anti-inﬂammatory activity) 86.
|Cabazitaxel and thymoquinone co-loaded lipospheres||In-vitro: MCF-7, MDA-MB-231 breast cancer cells||In-vitro: A dose-dependent reduction in cell viability of MCF-7 and MDA-MB-231 breast cancer cell lines upon treatment with Cabazitaxel-thumoquinone loaded nanoparticles.
Cell cycle analysis: Concentration-dependent percent increase in sub G1 population upon treatment with lipospheres loaded with combination drug.
Apoptosis: Increase in percentage of early apoptotic cells upon treatment with combination drugs 87.
|Hyaluronic acid-coated cabazitaxel loaded solid lipid nanoparticles||In-vitro: MCF-7 breast cancer cells||In-vitro: Concentration-dependent decrease in cell viability upon treatment with cabazitaxel nanoparticles with enhanced cellular uptake as compared to controls 88.|
|Cabazitaxel loaded polymeric micelles||In-vitro: 4T1 metastatic breast cancer cells||In-vitro: Inhibition of 4T1 cell migration upon treatment with cabazitaxel loaded polymeric micelles.
In-vivo: Inhibition of tumor growth upon treatment with Cabazitaxel loaded polymeric micelles 89.
Mode of Action of Taxanes: The mode of action of taxanes on cells can broadly divide into two types depending on its action pattern namely (a) Mitotic action and (b) Apoptotic action.
(a) Mitotic Action: This type of action is centered on mitotis where taxanes interact with the microtubules associated with the mitotic process. Taxanes, namely Docetaxel and Paclitaxel have similar mechanisms of action. Both of drugs have a stabilizing effect on microtubules on cells which counteract their depolymerization. This results in inhibition of correct separation of two identical sets of chromosomes and their consequent transfer during cell division. Docetaxel and Paclitaxel thus result in blockage of cell mitosis, ultimately leading to cell death 90. It is reported that Paclitaxel promotes microtubule polymerization and arrest mitosis through activation of spindle assembly checkpoint and keeping a small number of unattached kinetochores to the microtubules finally delaying mitotic metaphase progression and inhibiting anaphase prompting complex 91.
Moreover, at higher concentrations, Paclitaxel is reported to suppress microtubule minus-end detachment from the centrosomes 92. On a molecular level, taxol is reportedly to bind to a pocket in β-tubulin that faces microtubule lumen and is near the lateral interface between protofilaments, thereby affecting normal function and cellular processes 93 Fig. 6. The binding of Paclitaxel to the β-tubulin subunit results in the stabilization of microtubules through induction of conformational changes of the M-loop of β- tubulin, which results in more stable lateral interaction between adjacent protofilaments thereby changing microtubule dynamics and inducing mitotic block 94. Cabazitaxel also possess a similar mode of action. The molecule binds to tubulin thereby promoting its assembly microtubule assembly and simultaneously inhibiting dis-assembly. This results in the stabilization of microtubules, interference of mitotic and interphase cellular functions, halting of cell cycle progression at metaphase, thereby triggering apoptosis of cancer cells 95.
FIG. 6: REPRESENTATION OF SITE OF ACTION OF PACLITAXEL IN THE MICROTUBULE. (A) MICROTUBULE CONSISTING OF ALPHA AND BETA SUBUNIT OF TUBULIN WITH PACLITAXEL (IN RED TRIANGLE) ATTACHED TO INNER FACE OF BETA SUBUNIT. (B) A TUBULIN HETERODIMER SHOWING ALPHA AND BETA SUBUNIT. (C) A SECTIONAL VIEW OF MICROTUBULE SHOWING THE ATTACHMENT PATTERN PACLITAXEL ALONG THE WALL OF INNER LUMEN. (D) MOLECULAR STRUCTURE OF PACLITAXEL
(b) Apoptotic Action: Apoptotic action is quite diverse and includes the interaction of taxanes with various proteins and enzymes which are involved in the cell cycle, apoptosis, and cell death. Increased reactive oxygen species (ROS) is one of the earliest events of apoptosis and is brought about by Paclitaxel 96. Taxanes are also reported to initiate a decrease in mitochondrial membrane potential (ΔΨm). It is reported from a study that Paclitaxel induces the opening of mitochondrial membrane permeability pore resulting in release of calcium from mitochondria 97. In addition to it, Paclitaxel also results in the release of cytochrome c from mitochondria 98. Caspases are the family of endoproteases that play an important role in cell inflammation and cell death 99. Taxanes also activate caspases, thus initiating cell death and apoptosis 100. B-cell lymphoma (Bcl-2) is the key protein that regulates programmed cell death and apoptosis 101.
They may be divided into two major groups, namely (a) antiapoptotic protein (BCL-2, BCL-XL, MCL-1, BFL-1, BCL-W), and (b) proapoptotic proteins (BAK, BAX) 102. During apoptosis or cell death, oligomerization of pro-apoptotic effector proteins on the outer wall of the mitochondrial membrane results in mitochondrial membrane leakage and release of cytochrome c 103. The apoptosis in cancer cells is further induced by phosphorylation and inactivation of antiapoptotic Bcl-2 by Paclitaxel 104. Along with Bcl-2, p53 also plays a major role in the apoptotic process. The TP53 is the most frequently mutated gene associated to human cancers, which result in the production of mutant p53 proteins with loss in tumour suppression properties and concomitant gain of new oncogenic properties along with deregulated cell proliferation increased chemoresistance and altered tissue architecture 105.
It is an important tumor suppressor gene that regulates downstream expression of other genes involved in DNA repair, cell cycle arrest, and apoptosis 106. It is reported that Paclitaxel act as a p53 inducers, thereby enhancing the apoptotic process 107. A universal cell cycle inhibitor controlled by p53 is p21 108. It is regarded as a universal cyclin-dependent kinase (CDK) inhibitor and physically interacts and inhibits cyclin-CDK2, cyclin-CDK1, cyclin-CDK4/6 complexes thus regulate progression of the cell cycle during G1 and S phases 109. It is reported that Paclitaxel results in an increase of expression p21 through up-regulation of p53 110. Fig. 7 illustrates the various mechanism of action of taxanes leading to cell cycle arrest, cell death, and apoptosis.
FIG. 7: SCHEMATIC REPRESENTATION OF MODE OF ACTION OF TAXANES ON A CANCER CELL. (1) TAXANES DIRECTLY INTERACT WITH MICROTUBULE RESULTING IN THEIR STABILIZATION AND INHIBITING DEPOLYMERIZATION. THIS ULTIMATELY RESULTS IN MITOTIC ARREST AND EVENTUALLY CELL DEATH. (2) TAXANES RESULTS IN DECREASE IN MITOCHONDRIAL MEMBRANE POTENTIAL (ΔΨm) RESULTING IN LEAKAGE OF CYTOCHROME C IN THE CYTOSOL WHICH PARTICIPATES IN APOPTOTIC PROCESS. UPREGULATION OF CASPASE (3) AND DOWN REGULATION OF ANTIAPOPTOTIC Bcl-2 (4) IS ALSO BROUGHT ABOUT BY TAXANES ALL OF WHICH ADDS UP TO THE APOPTOTIC PROCESS. TAXANES ALSO INDUCE THE EXPRESSION OF p53, p21 (5) AND INHIBITS CYCLIN CDK COMPLEXES (6) THUS INHIBITING THE CELL DIVISION
Metabolism of Taxanes: Taxanes are primarily metabolized in the liver and primarily eliminated through biliary excretion via faeces 111. Taxanes are metabolized by hepatic cytochrome P450 (CYP450) enzyme systems 112. The major metabolites of Paclitaxel are 3’-p-hydroxy-paclitaxel, and 6α-hydroxypaclitaxel which are produced by CYP3A4 and CYP2C8, respectively 113. The oxidation of the tertiary butyl group on the synthetic side chain of docetaxel forms the main metabolic pathway in which CYP3A (3A4 and 3A5) family of cytochrome P450 enzymes plays the key role in the biotransformation 114. Cabazitaxel is also metabolized in the liver by the same family of cytochrome P450 enzyme system 115. Seven plasma metabolites of cabazitaxel are detected 116. Cabazitaxel is mainly excreted through faeces and a minor percentage through kidney 117.
Evolution in Formulation: Taxanes have been widely used as drugs for combating cancers. They act as potent mitosis inhibitors by interacting with the tubulin. The characteristic of the taxane skeleton is 10-baccatin III or 10-deacetyl baccatin III, which are bulky with poor aqueous solubility 118. Thus excipients such as Cremophor EL and ethanol for Paclitaxel 119, polysorbate 80 (Tween 80) for docetaxel 120, polysorbate, ethanol and citric acid for Cabazitaxel 121 are used. Cremophor EL and polysorbate 80 have the capacity to entrap and solubilize taxane in water, forming micelles while citric acid acts as a pH stabilizing compound 122. The adverse effects of these excipients, such as hypersensitivity, hemolysis, and cholestasis have also been reported 123. Additionally, Paclitaxel forms the substrate of P-glycoprotein (P-gp), which actively pumps Paclitaxel out of the cells inducing drug resistance 124. To overcome this problem, P-gp inhibitors such as verapamil and PSC833 were co-administered with taxanes, often resulting in toxicity and/or alteration in pharmacokinetics 125.
Nano based delivery systems act as a promising component in drug delivery as they improve the solubility of hydrophobic drugs and have reduced toxicity 126. Abraxane ®, a paclitaxel albumin-bound nanoparticle formulations having particle size around 130nm, was approved in 2005 for treatment of metastatic breast cancer 127. The formulations are advantageous as the solubility of hydrophobic taxanes are enhanced through encapsulation by albumin nanoparticles. Additionally, albumin-bound paclitaxel are also easier to infuse in higher doses than the standard doses of Paclitaxel with the higher response, lower toxicities, and less infusion time 128. The reduced side effects of nanoparticles based Paclitaxel are largely due to the fact that they can escape the recognition of the reticuloendothelial system in the healthy tissues 129. Nab-Paclitaxel is also a cremophor free water-soluble albumin-based Paclitaxel formulation and consists of 130 nm albumin-paclitaxel nano-particles. Treatment with nab-paclitaxel results in improved tolerability and higher response rates as compared to solvent-based formulations in patients with advanced metastatic breast cancer and non-small lung cancer 130. Poly (lactic-co-glycolic acid) (PLGA) is a widely used biodegradable copolymer used for the development of paclitaxel delivery system 131. They are homopolymers based on poly (lactic acid) (PLA) and poly (glycolic acid) PGA and has been approved by the US Food and Drug Administration (USFDA) for medical applications 132. PLGA has very low toxicity because it undergoes hydrolysis into its monomers of glycolic acid and lactic acid, which in turn are endogenously metabolized by the human body through the Krebs cycle and finally eliminated as carbon dioxide and water 133. Presently, PLGA nanoparticles are modified by Chitosan for sustained drug release and enhanced drug toxicity 134.
Liposomal formulations of taxanes have also been formulated, developed, and well described 135. They are spherical lipid vesicles with a mean diameter of 100 nm and comprises of a hydrophobic phospholipid bilayer with or without cholesterol having an aqueous core 136. Liposomal drugs have a low immunogenicity, limited toxicity, ability to carry larger molecules to the target site and capacity to accumulate in target tissue with enhanced bio-distribution 137. Thus, the bulky hydrophobic paclitaxel molecule could be entrapped in liposomal phospholipid bilayer, and it’s positioning representing a more metastable stage tending towards crystalline form 138. LEP-LEU is a liposomal formulation, developed by NeoPharm Labs, consisting of Paclitaxel and is composed of dioleoylphosphatidylcholine (DOPC), cholesterol and cardiolipin in a molar ratio of 90:5:5 with final total lipid to drug molar ratio of 33:1 and achieving an 85% percent entrapment efficiency of Paclitaxel 139.
EndoTAG-1 is another formulation in which Paclitaxel is embedded in cationic liposomal membrane 140. It is composed of cationic lipid dioleoyloxypropyltrimethylammonium (DOTAP), neutral lipid DOPC, Paclitaxel in molar ratio 50:47:3 and is the first formulation of cationic carrying paclitaxel to be used in clinical trial 141. 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and cholesterol is also used as a constituent of liposome for delivery of paclitaxel 142. In addition to it, dipalmitoylphosphatidylcholine (DPPC), and distearoyl phosphatidylcholine (DSPC) are also used for liposome assembly 143. Stealth technology is also used for the delivery of taxane molecules. In This technology, flexible hydrophilic polymers such as polyethylene glycol (PEG) is used as a protective hydrophilic layer on the surface of the liposomes and results in a reduction of clearance from the reticuloendothelial system 144. Such stealth liposomes have a prolonged circulation time 145 and improved pharmacokinetic profile in comparison to the normal drug 146. The attachment of hydrophilic polymers chains on the liposomes can be either through physical adsorption or covalent bonding using lipid molecules chemically functionalized at the head group, such as dipalmitoyl-Sn-glycero-3-phosphoethanolamine-N-[mPEG-5000] (DPPE-PEG) 147. The stealth technology also enables the liposome to get undetected by mononuclear phagocyte system 148.
PEGylated liposomes have some side effects, including hand-foot syndrome, fatigue 149, and skin toxicity 150. Thus non-PEGylated liposomes were developed to avoid the side effects and, at the same time delivering the same benefits of PEGylated liposomes. Non-PEGylated Doxorubicin is now widely used for the delivery of Paclitaxel in the treatment of breast cancers 151.
CONCLUSION: It seems to be quite evident that the taxanes are constantly in upgradation mode both in terms of mechanistic aspects and clinical aspects. The avenues of up-gradation and improvisation of taxanes are wide open for further studies. Moreover, combination treatments (taxanes along with some other drugs) also require to be stressed upon to improve the efficacy and anticancer activity. This further opens the way for the exploration of new drugs from nature and natural resources plants being the only resort in this case.
From a botanical point of view, cultivation of Taxus sp requires more attention, and biotechnological approaches for mass production of taxanes through tissue culture techniques needs a primary focus. Treatment of cancer would be more accomplished if the affordability of the drugs is taken into consideration by the pharmaceutical industry and governmental policy. Reducing the prices of the drugs will not only make it more accessible to the people but also at the same time will play a distinct role as a popular anticancer medicine amongst the wide array of drugs. Thus, cost calculation of treatment should also form an important parameter along with drug development for the overall benefit of mankind, specifically with respect to the population of third world countries where the occurrence of cancers is going to an alarming level mainly triggered by pollution and haphazard lifestyle. Thus, taxanes form a group of a versatile compound that has acquired a place in the pharmaceutical world for the treatment of a wide array of cancer. However, opportunities for its further development both in terms of pharmacology and cost efficiency remain wide open for over benefit of patients and mankind.
ACKNOWLEDGEMENT: The author wishes to acknowledge Government General Degree College, Mohanpur, Paschim Medinipur, West Bengal -721436, for providing their library support and other logistic facilities in framing the review article.
CONFLICTS OF INTEREST: The author declares no conflict of interest.
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How to cite this article:
Sinha D: A review on taxanes: an important group of anticancer compound obtained from Taxus sp. Int J Pharm Sci & Res 2020; 11(5): 1969-85. doi: 10.13040/IJPSR.0975-8232.11(5).1969-85.
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Department of Botany, Government General Degree College, Mohanpur, Paschim Medinipur, West Bengal, India.
29 July 2019
27 December 2019
03 April 2020
01 May 2020