Review
Paclitaxel and immune system

https://doi.org/10.1016/j.ejps.2009.08.009Get rights and content

Abstract

Chemotherapy remains the mainstay of treatment for both early stage as well as metastatic tumors. Paclitaxel (PTX), a novel anticancer drug, is a prominent taxane which is active against a broad range of tumors that are generally considered to be refractory to conventional chemotherapy, with benefits gained in terms of overall survival and disease-free survival. PTX is initially characterized as a mitotic inhibitor, and its anti-neoplastic effect is derived from binding to tubulin and excessive microtubule stabilization. Interestingly, drugs traditionally used for tumor cytoreduction, can exert both positive and negative effects on the host's immune system. PTX also exerts effects on the immune system and displays immunomodulatory traits. For example, PTX is immunostimulatory against tumors and also regulates lymphocyte activation suggesting that apart from promoting inhibition in cell division, it also has some other features and mechanisms which need to be taken into account. The present article reviews the clinical and experimental findings with regard to the effects of PTX on the immune cells including macrophages, dendritic cells (DCs), natural killer (NK) cells, and T and B lymphocytes together with its clinical applications in autoimmune disorders and organ transplantation which reflect greater therapeutic application of PTX beyond tumor chemotherapy.

Introduction

Taxanes represent an important and a novel class of anticancer agents that exhibit cytotoxic effects against a broad range of tumors (Clavarezza et al., 2006, Consolini et al., 1998, Dang and Hudis, 2006, De Laurentiis et al., 2008, Hernandez-Vargas et al., 2007, Hortobagyi, 1999). At present, paclitaxel (Taxol) and docetaxel (Taxotere) are the two clinically available representatives of taxanes. For consistency in this review, we will use the generic name ‘paclitaxel’ when referring to Taxol. Paclitaxel (PTX) has achieved prominence in clinical oncology for its efficacy against a wide range of tumors (Azzoli et al., 2007, Kubo et al., 2005, Vassileva et al., 2008). PTX, initially extracted from the bark of Pacific Yew Taxus brevifolia trees has been reported to be the first compound with a taxane ring and possessing anti-tumor activity (Wani et al., 1971). Anticancer agents target microtubules at the sub-cellular level (Jordan and Wilson, 2004). Microtubules perform important functions in cellular activities such as maintenance of cell shape, movement, signaling, division and mitosis. The pharmacologic interactions of drugs with microtubules cause disruption of the equilibrium within the microtubular system (Dustin, 1980) which in turn, would be expected to disrupt cell division and other normal cellular activities in which microtubules are involved. PTX exerts tumoricidal effect by preventing cytoskeletal microtubule depolymerization to free tubulin and thus, distrupts the balance between polymerization and depolymerization, which ultimately arrests the proliferation of neoplastic cells (Parness and Horwitz, 1981, Schiff et al., 1979, Spencer and Faulds, 1994). Indeed, PTX binds with β-tubulin to stabilize microtubule structure and stops cell cycle at G2/M mitotic interface (Donaldson et al., 1994, Lin et al., 1998). As immune cells are capable of destroying chemotherapy-resistant tumor cells, therefore, one of the strategies in ongoing clinical protocols to deal with tumors is the enhancement of immunological response. Strikingly, an emerging body of data suggests that PTX also exerts effects on immune system by stimulating anti-tumor and anti-autoimmunity effects (Cao et al., 2000, Tsavaris et al., 2002), supporting the idea that PTX suppresses the tumor through several mechanisms and not solely by inhibiting cell division. In this review, we discuss the effects of PTX on immune cells including macrophages, dendritic cells (DCs), natural killer (NK) cells, effector T-cells, regulatory T-cells (Tregs), and B-cells. In addition, we also discuss the clinical application of PTX to regulate immune system in autoimmunity and transplantation, indicating that PTX has a greater potential rather than being simply an anti-mitotic agent.

Section snippets

Tumor and immune system

It has been a matter of debate whether the immune system controls the neoplastic progression positively or negatively (Dunn et al., 2004a)? The concept of cancer immunosurveillance describes that the recognition and destruction of transformed cells is one of the physiologic functions of the immune system. Adaptive and innate immune cells not only participate in the surveillance, but also involve in the elimination of tumor cells. Cell-mediated innate immunity as well as adaptive immunity both

PTX and macrophages

Macrophages are found in all body tissues and constitute a host-wide effector system to perform a wide array of different functions, such as antigen presentation, phagocytosis of pathogens, immune surveillance and defense against tumors. Macrophages can kill tumor cells by several mechanisms, same as found in microbes, which include the release of lysosomal enzymes and nitric oxide (NO). Further, macrophages can destroy tumor cells in tissue culture by infiltrating into tumor mass through the

Clinical application of PTX in autoimmune disorders and transplantation

In addition to anti-neoplastic ability, PTX may be used as potential agent to treat autoimmune disorders and transplantation. In autoimmune disorders, the effect of PTX was reported in T-cell-dependent model of CIA in rats in which PTX suppressed the induction and caused the progression of pre-existing arthritis (Arsenault et al., 2000, Brahn et al., 1994). PTX also inhibited synovitis and neovascularization in joint spaces in CIA rats (Arsenault et al., 1998). PTX arrests cell cycle at G2/M

Concluding remarks and perspectives

PTX shows multiple actions on immune system by exerting different effects on immune cells. It regulates the production of various cytokines and stimulates/inhibits different lymphocytes to exhibit inhibitory effects on neoplasia and autoimmune diseases. The reviewed clinical and experimental studies clearly suggest that a drug-based strategy such as PTX may effectively exert cytotoxic activity against a range of neoplasms by promoting anti-tumor immune responses. PTX has both immunostimulatory

Acknowledgements

We thank the many researchers who have contributed to our current understanding of paclitaxel. The authors are supported by Higher Education Commission (HEC) of Pakistan.

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