Neurochemical Research (2019) 44:1796–1806 https://doi.org/10.1007/s11064-019-02837-x REVIEW Noscapine, a Non‑addictive Opioid and Microtubule‑Inhibitor in Potential Treatment of Glioblastoma Meric A. Altinoz1,2 · Gulacti Topcu3 · Ahmet Hacimuftuoglu4 · Alp Ozpinar5 · Aysel Ozpinar1 · Emily Hacker5 · İlhan Elmaci6 Received: 5 April 2019 / Revised: 12 June 2019 / Accepted: 21 June 2019 / Published online: 10 July 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Noscapine is a phthalide isoquinoline alkaloid that easily traverses the blood brain barrier and has been used for years as an antitussive agent with high safety. Despite binding opioid receptors, noscapine lacks signifcant hypnotic and euphoric efects rendering it safe in terms of addictive potential. In 1954, Hans Lettré frst described noscapine as a mitotic poison. The drug was later tested for cancer treatment in the early 1960’s, yet no efect was observed likely as a result of its short biological half-life and limited water solubility. Since 1998, it has regained interest thanks to studies from Emory University, which showed its anticancer activity in animal models with negligible toxicity. In contrast to other microtubule-inhibitors, noscapine does not afect the total intracellular tubulin polymer mass. Instead, it forces the microtubules to spend an increased amount of time in a paused state leading to arrest in mitosis and subsequently inducing mitotic slippage/mitotic catastrophe/apop- tosis. In experimental models, noscapine does not induce peripheral neuropathy, which is common with other microtubule inhibitors. Noscapine also inhibits tumor growth and enhances cancer chemosensitivity via selective blockage of NF-κB, an important transcription factor in glioblastoma pathogenesis. Due to their anticancer activities and high penetration through the blood–brain barrier, noscapine analogues strongly deserve further study in various animal models of glioblastoma as potential candidates for future patient therapy. Keywords Noscapine · Microtubule · Glial tumor · Glioblastoma Introduction resection, radiotherapy and adjuvant temozolomide chemo- therapy, only provide a median survival of ~ 15 months in High-grade glial tumors continue to demonstrate large rates patients with glioblastoma multiforme [1]. Despite exten- of mortality even with aggressive management. The most sive basic and clinical study, there exist only a very limited recent treatment standards, which include maximum surgical number of medicines that are efective in the treatment of neuro-oncological diseases. However, efective remedies * Meric A. Altinoz could be just within our reach as the potential for relatively [email protected] inexpensive drugs to exert versatile benefts in a number of diferent disease conditions may yet to be discovered. 1 Department of Medical Biochemistry, Acibadem University, In this review, we have focused on such a drug, noscapine, Istanbul, Turkey which harbours tremendous potential to be developed as a 2 Department of Psychiatry, Maastricht University, Maastricht, new agent in neuro-oncological diseases. The second refer- The Netherlands ence of this manuscript is also a review, yet it deals mostly 3 Department of Pharmacy, Bezmi Alem University, Istanbul, with the history and general clinical applications of the drug. Turkey Previously thus far, there has been no review with a selective 4 Department of Medical Pharmacology, Erzurum Ataturk focus on the potency of noscapine in gliomas. At frst, we University, Erzurum, Turkey will outline the general chemistry and history of noscapine. 5 Department of Neurosurgery, University of Pittsburgh, Pittsburgh, USA 6 Department of Neurosurgery, Acibadem Hospital, Istanbul, Turkey Vol:.(1234567890)1 3 Neurochemical Research (2019) 44:1796–1806 1797 Noscapine. General Chemistry and History narcosine, narcotine, nectodon, nospen, anarcotine, terbe- of the Drug nol, and tusscapine [2, 3]. After morphine, noscapine is the most abundant of the alkaloids of Papaversomniferum Noscapine is a phthalide-isoquinoline alkaloid of Papaver- and was among the frst of the alkaloids to be isolated [4]. somniferum (Fig. 1) and its IUPAC name is (3S)-6,7-dimeth- French chemist Charles Derosne isolated noscapine from oxy-3-[(5R)-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3] opium in 1803 and named the compound ‘ ‘sel narcotique dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one de Derosne’ ’ (Derosne’s narcotic salt). Pierre Jean Robi- [2]. Phthalide-isoquinoline compounds exist in the plant quet later demonstrated that Derosne’s narcotic salt was not families Papaveraceae, Berberidaceae, and Ranunculaceae, a morphine meconate, but rather a new molecule that he but noscapine and the related compound narcotoline are named narcotine (former name for noscapine). Noscapine’s confned to members of the genus Papaver. Noscapine has molecular weight is 413.42 g/mol and the molecular formula many other names including capval, coscopin, narcompren, is C22H23NO7. It is a white powder that is bitter and odorless. Noscapine is insoluble in water, mostly insoluble in vegeta- ble oils, slightly soluble in alcohol and ether, and soluble in benzene and acetone [2]. A historical time line of noscap- ine’s actions is provided in the second reference of this manuscript. Briefy, the main developments are as follows: in 1954, Hans Lettré defned noscapine as a relatively weak mitotic poison whose anti-mitotic activity acted synergisti- cally with that of N-methyl-colchicine. In 1997, noscapine’s efcacy to antagonize dopamine synthesis in PC12 cells was revealed. In 1998, mouse models demonstrated the potent in vivo antineoplastic activity of noscapine against various cancers. In 2003, noscapine’s antistroke efcacy was found. In 2003, brominated noscapine analogs were synthesized and demonstrated a prominent ability to block mitosis in malignant cells. In 2010, studies demonstrated that noscap- ine might alleviate the disease burden in polycystic ovarian syndrome rodent models. In 2014, third-generation hydro- philic derivatives of noscapine were synthesized. Figure 2 depicts the general structure of noscapine and summarizes Fig. 1 Papaver somniferum its anticancer mechanisms. Fig. 2 Putative action mechanisms of noscapine in glioblastoma 1 3 1798 Neurochemical Research (2019) 44:1796–1806 In 1930, noscapine was discovered as an antitussive agent 10]. Noscapine has a short biological half-life, poor absorp- that did not cause signifcant secondary sedative, hypnotic, tion, and limited water solubility, which make it difcult to or euphoric efects. As a result, the drug is nonaddictive harness as an oral anticancer drug [2]. Hence, recent stud- and carries mild central nervous system activity similar ies have focued on developing novel techniques for targeted to that of papaverine [2, 4]. This distinguishes noscapine delivery and extended serum presence of noscapine. Addi- from codeine, which is frequently abused due to its addic- tional research has been performed to discover novel noscap- tive properties as a result of its metabolite codeine-6-glu- ine analogues with higher water solubility and higher tumor- curonide [5]. Activity on the μ-opioid receptor causes the icidal activity at lower dosages [2]. Following explaining the clinical efects associated with opioids [6]. However, data chemistry and biosafety of noscapine, below, we will outline indicates that noscapine may bind a diferent opioid recep- its main mechanism of action–inhibition of microtubules. tor and not the μ-opioid receptor like the stronger addic- tive opioids [2]. In support of this theory is the fnding that noscapine lacks antitussive properties in a dose-dependent Noscapine: Main Mechanism of Action manner when the σ-opioid receptor is antagonized [7]. as a Selective Microtubule Inhibitor Among neurotrasmitter-related structures, indole amines in Cancer Cells and carbolines also exert afnity for noscapine sites [4]. Noscapine hinders carbachol-stimulated phosphoinositide Dynamic polymerization and depolymerization of microtu- turnover in guinea pig and rat brain slices, with structural bules is essential for the formation of the mitotic spindle, a analogs (hydrastein, bicuculline, papaverine) harbouring key step in cell proliferation. Thus, this known property has similar potencies for binding to noscapine binding sites and led to a prominent interest in discovering small organic mol- blocking phosphoinositide turnover [4]. Noscapine and its ecules that modulate the dynamics of microtubules in order derivatives also prominently increase the ability of forskolin to block cancer cell mitosis [8]. Mitosis necessitates a fne to augment cAMP levels in brain slices [4]. Noscapine has control of microtubule dynamics for generation of tension chemical moieties similar to those of the microtubule inhib- across kinetochore pairs and proper chromosome alignment. itory drugs colchicine and podophyllotoxin, which led to During mitosis, spindle microtubules are 10–100 fold more studies about its possible employment as an anticancer agent dynamic than interphase microtubules, which allows efec- [8]. Noscapine undergoes extensive ‘frst pass’ metabolism tive capturing, alignment, and segregation of chromosomes mainly by C–C cleavage, O-demethylation and cleavage [11]. Hence, even minor alterations of microtubule dynamics of methylenedioxy group in humans. Its main metabolites can signal the spindle checkpoint to hinder anaphase onset include cotarnine, hydrocotarnine, and meconine,