Therapeutic strategies to overcome taxane resistance in cancer
Graphical abstract
Introduction
Cancer is the second-largest cause of mortality after cardiovascular disease in the world (World Health Organization, 2017) and is a burden to cancer patients and society. Despite significant medical advances in the treatment of cancer, drug resistance is the key obstacle for obtaining curative cancer therapy. A major obstacle towards efficacious cancer treatment is the emergence of multidrug resistance (MDR) (Saraswathy and Gong, 2013; Cui et al., 2018; Li et al., 2016; Livney and Assaraf, 2013; Robey et al., 2018; Assaraf et al., 2019; Andrei et al., 2020; Kopecka et al., 2020; Wang et al., 2021), which represents an emerging challenge to public health worldwide and is a major contributor to cancer-related mortality due to the abrogation of the efficacy of chemotherapy (Alfarouk et al., 2015; Saraswathy and Gong, 2013; Nikolaou et al., 2018). Over the last three decades, drug resistance has been globally recognized as an outcome in patients treated with drugs that are no longer efficacious due to a variety of molecular mechanisms (Armando et al., 2020; Hamed et al., 2019; Nikolaou et al., 2018). Currently, combination therapies are one of the most efficacious and safest choices for treating cancer, as they are less likely to produce drug resistance and are more efficacious than monotherapeutic regimens (Sarkar et al., 2013; Byler et al., 2014; Heerboth et al., 2014). The molecular mechanisms underlying drug resistance in cancer cells include: 1) compartmentalization of drugs away from the cellular target; 2) overexpression of MDR efflux transporters of the ABC superfamily; 3) qualitative (i.e., mutations) or quantitative alterations in the cellular drug target; 4) increased metabolism of drugs that become less potent or completely inefficacious; 5) alterations in the tumor microenvironment (TME) that increase the probability of cancer cell survival; 6) increase in the repair of damaged DNA; 7) inhibition of cell death pathways and 8) evasion of the host immune response (Bar-Zeev et al., 2016; Mansoori et al., 2017; Assaraf et al., 2019; Zhitomirsky and Assaraf, 2016; Li et al., 2017; Ren et al., 2016; Meng et al., 2016; Yu et al., 2018).
Plants produce numerous secondary metabolites, including bioactive compounds, such as polyphenols, flavonoids, alkaloids, and brassinosteroids (Anand et al., 2019, 2020; Mohammed et al., 2021), that have anti-neoplastic efficacy (Ackova et al., 2019; Collado-Borrell et al., 2016; Ren et al., 2017; Tao et al., 2020). Furthermore, these metabolites have been used for the formulation of novel clinical compounds using nanotechnological approaches (Cao et al., 2013; Iravani and Varma, 2019; Iravania and Soufib, 2020). Interestingly, several plant-derived drugs (PDDs), including PTX, vincristine, vinblastine, vinorelbine, colchicine, epipodophyllotoxins (etoposide and teniposide), camptothecins (topotecan and irinotecan), curcumin, ampelopsin (dihydromyricetin), plumbagin, capsaicin and matrine, have been reported to be efficacious in the treatment of certain types of cancer (Cragg and Newman, 2013; Cao et al., 2018; Li et al., 2018; Russo, 2019; Zhang and Kanakkanthara, 2020). Moreover, PTX, vincristine, colchicine, topotecan, irinotecan, etoposide and teniposide have been approved by Food and Drug Administration (FDA) for the treatment of distinct cancers, including acute lymphoblastic leukemias, lymphomas, gastroesophageal, ovarian, endometrial, breast, prostate, lung, skin cancers, Kaposi’s sarcoma, cervical carcinoma head and neck cancers (Iqbal et al., 2017; Ijaz et al., 2018; Ashraf, 2020). Among the abovementioned compounds, PTX (Fig. 1A), which is a taxane diterpene isolated from the bark of Taxus brevifolia, is used to treat certain types of cancers (Bernabeu et al., 2017; McElroy and Jennewein, 2018; Yao et al., 2017). Its structure was first reported in 1971, and its efficacy was assessed in an in vivo mouse model of leukemia (Wani et al., 1971). PTX has been obtained from other sources, such as shells and the leaves of Corylus avellana L. (Ottaggio et al., 2008). Another taxane derivative, docetaxel (Fig. 1A), which is structurally similar to PTX, was extracted from Taxus baccata L., using a semisynthetic isolation approach, and was reported to have anti-neoplastic efficacy in lung and breast cancer cell lines (Bissery et al., 1995). Interestingly, PTX and docetaxel bind to a hydrophobic cleft in β-tubulin (Snyder et al., 2001); PTX and docetaxel produce G2/M cell cycle arrest and facilitate microtubule polymerization in certain cancer cells (Amin et al., 2009). Notably, PTX and taxanes exert their therapeutic efficacy by disruption of the mitotic spindle, mitosis slippage and inhibition of angiogenesis (Mosca et al., 2021).
These taxane-based anticancer drugs are used in the treatment of refractory ovarian cancer, small-cell lung cancer, metastatic breast cancer, advanced forms of Kaposi’s sarcoma, head and neck cancer and prostate cancer (Ojima et al., 2016; Yared and Tkaczuk, 2012). However, numerous studies have reported that the efficacy of PTX is significantly decreased or abolished in cancer cells because of the emergence of MDR (Barbuti and Chen, 2015). The mechanisms underlying the resistance to chemotherapeutic drugs are multifactorial but resistance to PTX results from various alterations in tubulin, including mutations that decrease the binding of PTX, posttranslational modifications and an increase in the expression of certain MDR efflux transporters such as P-gp (Liao et al., 2019). Moreover, cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation also mediate the acquisition of PTX resistance (Mosca et al., 2021).
In this review, several preclinical studies related to the reversal of PTX resistance are described in detail by discussing the efficacy of drug combinations involving P-gp inhibitors and plant-derived compounds. The plant-derived compound, ferulic acid (4-hydroxy-3-methoxycinnamic acid), reverses the ABCB1 (ATP-binding cassette subfamily B member 1)-mediated resistance to PTX in the MDR KB ChR8−5 cell lines (Muthusamy et al., 2016). Furthermore, ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, reverses PTX resistance in ABCB1- and ABCC10-overexpressing human papillomavirus-related endocervical adenocarcinoma KB-C2 cell xenograft, at a dose of 30 mg/kg (Zhang et al., 2017a). However, based on Western blot analysis, ibrutinib (5 μM for 72 h) did not significantly alter the expression of the ABCB1 (P-gp) and ABCC10 (MRP7) transporter proteins. Thus, the combination of ibrutinib and PTX may represent a novel strategy to reverse PTX resistance. Recently, it has been reported that the proteasome inhibitor, carfilzomib (CFZ, 100 nM), attenuates PTX resistance in PTX-resistant KYSE-30 human esophageal squamous cell carcinoma cells by activating hypoxia-inducible factor 1 (HIF-1) signaling (Wu et al., 2018). In vitro studies and preclinical data indicate that the combination of SNOH-3, an inhibitor of histone deacetylase (HDAC1, 3 and 6) and PTX, significantly decreased resistance to PTX by downregulating HDAC expression, thereby activating apoptosis and inhibiting angiogenesis in a concentration-dependent manner (2.5–40 μM). An isobologram analysis indicated a synergistic interaction between SNOH-3 and PTX, with a CI value of 0.366 in lung cancer cells (Wang et al., 2016). It should be noted that SNOH-3, which was more potent than the FDA-approved HDAC inhibitor, SAHA, in inhibiting HDAC activity, induced cell apoptosis, and suppressed cell migration, invasion and angiogenesis (Wu et al., 2018).
The co-administration of a liposomal formulation of tariquidar (a well-established P-gp inhibitor) and PTX (1.0 and 1.5 mg/kg, respectively), reversed PTX resistance in ovarian cancer HeyA8-MDR xenografts (Zhang et al., 2016). However, the lack of selectivity for cancer cells remains a major concern for the use of combination therapy, as this would cause the accumulation of taxanes in normal cells and tissues, resulting in serious adverse or toxic effects (Guo et al., 2017b). Recent pharmacogenomics data from HCT 116 colon cancer cells have shown that alsterpaullone, a CDK1 inhibitor (Schultz et al., 1999), could be used in combination with other anticancer drugs to overcome PTX chemoresistance (Bae et al., 2015). Tumor-suppressor proteins and Bcl-2 family genes influence apoptotic pathways either directly or indirectly (Pfeffer and Singh, 2018; Warren et al., 2019). Therefore, the ratio of anti-apoptotic to pro-apoptotic proteins can produce PTX sensitivity or resistance in cancer cells.
It is known that PTX resistance occurs by different mechanisms (Mosca et al., 2021). Thus, the current review provides an: 1) overview of the various mechanisms that produce PTX and docetaxel resistance; 2) outline of the in vitro experimental data acquired from comprehensive analyses performed using different human cancer cell lines and highlights pharmacological studies conducted to overcome PTX and docetaxel resistance based on the inhibition of efflux pumps or the modulation of transporter activity. We also discuss future research areas regarding the reversal of drug resistance based on pharmacological compounds and their possible role in the discovery of new drugs.
Section snippets
Methodology
Relevant information and scientific data were collected and retrieved from different online sources/servers or databases, including PubMed, Google Scholar, ResearchGate, Scopus, and Science Direct. The scientific names of plants were validated using the Tropicos website (https://www.tropicos.org/home). Chemical structures were retrieved from the web deposits of ChemSpider (http://www.chemspider.com/) and PubChem (https://pubchem.ncbi.nlm.nih.gov/). The search strings contained keywords such as
Molecular mechanisms of paclitaxel resistance
The major mechanisms that mediate PTX resistance include qualitative and quantitative alterations of: 1) microtubules (MTs), changes in the expression of tubulin proteins (microtubule-associated protein 2 (MAP2), MAP4, Tau, kinesin, centriole, cilia, and spindle-associated protein (CCSAP) and Eg5); 2) certain drug transporters; 3) the levels of cell cycle-related proteins, cell cycle alterations (particularly late G2/M phase), changes in cyclin A1 expression, and alterations in kinases,
Strategies to overcome paclitaxel and docetaxel resistance using novel compounds
Over the last several decades, various therapeutic strategies have been developed to overcome MDR (Saraswathy and Gong, 2013; Cui et al., 2018; Lage, 2016; Lin et al., 2016; Zhang et al., 2021; Li et al., 2020a, 2020b, 2020c; Lepeltier et al., 2020; Narayanan et al., 2020; Cui et al., 2018; Bar-Zeev et al., 2017; Li et al., 2016; Shapira et al., 2011). As previously mentioned, the resistance of certain cancer cells to PTX can result from the overexpression of the multidrug efflux pump, P-gp.
Natural compound-mediated reversal of resistance
Natural compounds have served as a key source for the discovery of new lead compounds and account for approximately 50 % of pharmaceuticals worldwide (Newman and Cragg, 2016; Anand et al., 2019). Currently, in the context of oncology, compounds derived from natural products comprise more than 70 % of all the currently available anticancer drugs (Harvey et al., 2015). Naturally, derived compounds (e.g., secondary metabolites, phytochemicals, fungal, and marine compounds) have been identified as
Conclusions and future perspectives
PTX- and docetaxel-mediated drug resistance is a complex process that is caused by alterations at the genetic and biochemical levels. PTX and docetaxel interact with tubulin proteins and thus, various types of tubulin modifications constitute an integral part of the reversal of drug resistance, as was discussed in the current review. Genetic modifications related to p53 or MDM2 overexpression induce resistance to PTX and docetaxel in certain types of cancer. Furthermore, it is well established
Funding
AD is supported by the “Faculty Research and Professional Development Fund” (FRPDF) for financial assistance from Presidency University, Kolkata, India.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
Authors are thankful to their respective departments/institutes for providing space and other necessary facilities which helped to draft this manuscript.
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- 1
Present address: Bencos Research Solutions, New Link Road, Andheri West, Mumbai-400053, Maharashtra, India.
- 2
These authors have equally contributed to this review article.