Medical Hypotheses xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy

Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach) Devina Verma, Tahir Khuroo, Sushama Talegaonkar, Zeenat Iqbal ⇑ Dept of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India

a r t i c l e

i n f o

Article history: Received 14 December 2014 Accepted 1 March 2015 Available online xxxx

a b s t r a c t An insight into the complex cancer pathophysiology reveals that a dependable amelioration of the disease could only be envisaged with a multipronged treatment approach. It is highly evident that singular chemotherapeutic agents used in clinical practice have shown limitations like severe side effects, MDR and are often associated with poor QOL while combinations of drugs have yielded better therapeutic outcomes. The current hypothesis takes it a step forward wherein a chemotherapeutic agent is combined with a natural chemosensitizer, both loaded into a nanopotentiated particulate system, which would eventually deliver the drug cargo at the target site with certitude. The encapsulated natural bioactive would then favorably act on the tumor milieu through multiple portals and chemosensibilize the cells towards cytotoxic action of the synthetic drug moiety. This 2C (chemotherapeutic and chemosensitizer) approach along with nanosystem’s attributes like high payload, prolonged action and diminished side effects would proffer a more dependable treatment modality. In conclusion, the proposed system would be a value addition to the currently available armamentarium of cancer treatment tools. Ó 2015 Elsevier Ltd. All rights reserved.

Introduction The unraveling of the cancer hallmarks in a highly received review by Hahnemann et al. and later on a revisit to it [1,2] has led to an unprecedented interest and astounding progression in cancer therapeutic research. Nonetheless, the complex pathological underpinnings of the disease, drying up drug pipeline and associated suboptimal drug responses has made cancer amelioration a huge challenge. It is painfully evident that chemotherapy, though being the backbone of treatment of disseminated cancer is still continuing to face major challenges. To reiterate, the challenges include firstly the unresponsiveness of the resilient tumor cell as a result of chemoresistance and secondly their specific delivery to the cancer cells restricting their toxic effects to tumor cell thereby safeguarding the normal cells against the undue damaging effect. The phenomenon of chemoresistance has proven to be the most dominant reason for the failure of chemotherapy limiting the effectiveness of the current chemotherapeutics and posing a serious hurdle towards synthesis of newer chemical entities for cancer therapy [3,4]. Some tumors are inherently resistant to cytotoxic drugs while others develop resistance over time [5] which causes aggressive relapses in majority of cancer patients leading to high rate of mortality [6]. Briefly, chemoresistance is a phenomenon ⇑ Corresponding author. Tel.: +91 9811733016; fax: +91 26059663. E-mail address: [email protected] (Z. Iqbal).

wherein the tumor cell becomes resistant to structurally and mechanistically different anticancer agents due to various alterations at cellular levels consequently resulting in unresponsiveness to cancer chemotherapy [7]. By far five vital mechanism have been investigated which causes resistance in a malignant cell (1) the increased expression of ATP-binding cassette (ABC) efflux transporters, (2) changes in the level of protein targets (3) enhanced DNA repair (4) overexpression of antiapoptotic proteins or downregulation of proapoptotic proteins (5) detoxification by phase II conjugating enzymes, such as glutathione S-transferases and UDP-glucuronosyltransferases [8,9]. Chemosensibilization of the cell therefore becomes the need of the hour necessitating the use of an agent that sensitize the tumor cell and increase its sensitivity to chemotherapy. Numerous agents both synthetic and natural have been investigated to possess the ability to reverse tumor resistance. Although a number of synthetic agents have been used over the past they have been proven to be largely ineffective leading to firstly, increase drug burden because of a relatively high dose required to produce the desired chemosensitization effect and secondly, influencing the pharmacokinetics of the antineoplastic drug resulting in increased plasma levels beyond acceptable limit [10,11]. Natural bioactive agents can therefore prove to be savior, with a large repertoire of data indicating its applicability as chemosensitizing agents [12,13]. Many natural agents have been investigated in this regard and are found to act via several mechanisms such as efflux protein modulation, upregulation of apoptotic

http://dx.doi.org/10.1016/j.mehy.2015.03.003 0306-9877/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Verma D et al. Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach). Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.03.003

2

D. Verma et al. / Medical Hypotheses xxx (2015) xxx–xxx

proteins and downregulation of antiapoptotic proteins to reverse drug resistance and increase drug sensitivity [14,15]. Unlike the synthetic agents they pose no harm to the normal cells and are thus devoid of the offsite toxicity common to the nonspecific anticancer agents [16]. Moreover they have shown to interfere with multiple signaling pathways of cancer thus triggering cell death apart from chemosensitizing tumor cell. [17,18]. Therefore, a synergistic cocktail of the chemotherapeutic and chemosensitizing agents can be an efficient strategy to obtain a pleotropic effect on cancer alongwith countering multidrug resistance. However pharmaceutical hurdles such as bioavailability, poor aqueous solubility, stability limit the clinical translation of many active moieties [19]. Here nanotechnology based smart delivery system can offer great promise to cancer patients. Therefore to overcome limitations of conventional drug carriers as well as biological barriers, ligand based nanoparticulate with benefits such as (1) stability of the encapsulated drugs in the polymer matrix (2) temporal release of the actives (3) improved solubility (4) lower ED50 (5) improved pharmacokinetic (6) vehicle uniformity (7) ratiometric drug loading (8) evasion of uptake by reticuloendothelial system and mononuclear phagocytes (9) increased cellular uptake and intracellular accumulation [20] are in great demand. Hypothesis Our study therefore hypothesizes the targeting of this multifactorial disease via a ‘‘2C approach’’ i.e. the dual delivery of a synthetic chemotherapeutic agent and a natural chemosensitizing agent in a surface modified nanoparticulate system to achieve efficient delivery of the two agents at the targeted cancer site and enhance antitumor activity by targeting different pathways so as to obtain multipronged magic bullet for cancer. This study hypothesizes (1) enhanced sensitivity of cancer cell to chemotherapeutic agent by reversal of chemoresistance (2) synergistic effect of the cytotoxic drug and herbal chemosensitizer by targeting cancer cell via different mechanism (3) simultaneous and efficient delivery of the two moieties by means of a single nanoparticulate system (4) enhanced cellular uptake and prevention of offsite toxicity by modifying the surface of nanoparticle by means of a suitable ligand.

nanomedicines [30]. This often harnesses the potential of soft matter/biodegradable polymers to encapsulate the drug cargo and deliver it at the site of action by virtue of its small size, appropriate shape and ease of entering into the vasculature often referred to as enhanced permeation and retention (EPR) at the tumor site [31]. The proposed nanopotentiated 2C approach is an innovative take on using a synthetic antineoplastic drug along with the plant based chemosensitizer in a singular nanomatrix. Such a system would target cancer with a two pronged approach proving more beneficial than conventional combination therapy and also offering certain unique pharmaceutical advantages such as vehicle uniformity, improved drug sensitivity and synergistic effect [32,33]. An accentuated site specific performance of the purported system could be further accommodated by decorating the surface of the nanosystem with a suitable ligand which would then recognize its target thus resulting in receptor based internalization and eventually increasing its intracellular accumulation in the tumor cell [34] and ultimately leading to better cytotoxicity. Conclusion Conventional chemotherapy, despite being the mainstay of cancer treatment is far from successful in containing this monstrous disease and is marred with myriad deficiencies. The unique tumor physiology with its constitutive chemoresistance and nonselective delivery which harm the healthy cells, further add to the challenges of effective cancer therapy. Thus we expect that the combined modality or the 2C approach along with the nanotechnology as described in the above hypothesis will yield a multipronged tool to target this multifactorial disease and play a pivotal role in better cancer amelioration. Conflict of interest The authors declare no conflict of interest. Source of funding The authors would like to thank Indian Council of Medical Research, Government of India for providing Senior Research Fellowship.

Evaluation of the hypothesis A number of plant based bioactives such as curcumin, resveratrol, genistein, CAPE, emodin, flavopiridol, silymarin have been investigated for their chemosensitization effect and have reportedly elicited reversal of chemoresistance through simultaneous modulation of multiple pathways which are responsible for tumorigenesis [21–24]. Earlier reports have suggested that these bioactives have multiple foci of action both direct and indirect [25]. Henceforth combining them synergistically with synthetic chemotherapeutic drugs would yield a dependable therapeutic tool for circumventing cancer. Curcumin has augmented anticancer activity of gemcitabine and 5FU [26,27] while resveratrol has sensitized human cancer cell lines such as neuroblastoma, glioblastoma, and breast carcinoma, prostate carcinoma to chemotherapeutic agents such as doxorubicin, cytarabine, taxol, and methotrexate [28]. Another flavonoid, myricetin in combination of with 5-fluorouracil was found to increase tumor chemosensitivity of esophageal cancer cells [29]. The aforementioned combinations have been successfully used as conventional therapeutics, nonetheless has been marred by limitations like offsite toxicity and pharmaceutical issues such as drug solubility and stability. In the recent years, emergence of nanotechnology and its amalgamation with drug delivery has led to a novel premise of

References [1] Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57–70. [2] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. [3] Efferth T, Konkimalla VB, Sauerbrey A, Wang YF, Meinhardt S, Zintl F, et al. Prediction of broad spectrum resistance of tumors towards anticancer drugs. Clin Cancer Res 2008;14:2405–12. [4] Gillet JP, Gottesman MM. Overcoming multidrug resistance in cancer: 35 years after the discovery of ABCB1. Drug Resist Updat 2012;15(1):2–4. [5] Luqmani YA. Mechanisms of drug resistance in cancer chemotherapy. Med Princ Pract 2005;14(1):35–48. [6] Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol 2005;205(2):275–92. [7] Liu FS. Mechanisms of chemotherapeutic drug resistance in cancer therapy—a quick review. Taiwane J Obstet Gynecol 2009;48(3):239–44. [8] Gatti L, Zunino F. Overview of tumor cell chemoresistance mechanisms. Chemosensitivity: volume II. Humana Press; 2005. p. 127–48. [9] Abdullah LN, Chow EKH. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2013;2(1):1–9. [10] Krishna R, Mayer LD. Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci 2000;11:265–83. [11] Liscovitch M, Lavie Y. Cancer multidrug resistance: a review of recent drug discovery research. IDrugs 2002;5(4):349–55. [12] Vinod BS, Maliekal TT, Anto RJ. Phytochemicals as chemosensitizers: from molecular mechanism to clinical significance. Antioxid Redox Signal 2013;18(11):1307–48.

Please cite this article in press as: Verma D et al. Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach). Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.03.003

D. Verma et al. / Medical Hypotheses xxx (2015) xxx–xxx [13] Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal 2005;7(11–12):1630–47. [14] Erstad DJ, Cusack JC. Targeting the NF-jB pathway in cancer therapy. Surg Oncol Clin North Am 2013;22(4):705–46. [15] Eichhorn T, Efferth T. P-glycoprotein and its inhibition in tumors by phytochemicals derived from Chinese herbs. J Ethnopharmacol 2012;141(2): 557–70. [16] Rather MA, Bhat BA, Qurishi MA. Multicomponent phytotherapeutic approach gaining momentum: is the ‘‘one drug to fit all’’ model breaking down? Phytomedicine 2013;21(1):1–14. [17] Di Domenico F, Foppoli C, Coccia R, Perluigi M. Antioxidants in cervical cancer: chemopreventive and chemotherapeutic effects of polyphenols. Biochim Biophys Acta (BBA)-Mol Basis Dis 2012;1822(5):737–47. [18] Sarkar FH. Targeting multiple signal pathways by chemopreventive agents for cancer prevention and therapy1. Acta Pharmacol Sin 2007;28(9):1305–15. [19] Chen H, Khemtong C, Yang X, Chang X, Gao J. Nanonization strategies for poorly water-soluble drugs. Drug Discov Today 2011;16(7):354–60. [20] Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat Nanotechnol 2007;2(12):751–60. [21] Chen C, Zhou J, Ji C. Quercetin: a potential drug to reverse multidrug resistance. Life Sci 2010;87(11–12):333–8. [22] Xue X, Yu JL, Sun DQ, Zou W, Kong F, Wu J, et al. Curcumin as a multidrug resistance modulator—a quick review. Biomed Preventive Nutr 2013;3(2): 173–6. [23] Limtrakul P. Curcumin as chemosensitizer. The molecular targets and therapeutic uses of curcumin in health and disease. Springer US; 2007. p. 269–300. [24] Gupta SC, Kannappan R, Reuter S, Kim JH, Aggarwal BB. Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 2011;1215(1):150–60.

3

[25] Bhanot A, Sharma R, Noolvi MN. Natural sources as potential anti-cancer agents: a review. Int J Phytomedicine 2011;3(1):09–26. [26] Kanai M, Yoshimura K, Asada M, Imaizumi A, Suzuki C, Matsumoto S, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol 2011;68(1):157–64. [27] Tian F, Fan T, Zhang Y, Jiang Y, Zhang X. Curcumin potentiates the antitumor effects of 5-FU in treatment of esophageal squamous carcinoma cells through downregulating the activation of NF-jB signaling pathway in vitro and in vivo. Acta Biochim Biophys Sin 2012;44(10):847–55. [28] Fulda S, Debatin KM. Sensitization for anticancer drug- induced apoptosis by the chemopreventive agent resveratrol. Oncogene 2004;23:6702–11. [29] Wang L, Feng J, Chen X, Guo W, Du Y, Wang Y, et al. Myricetin enhance chemosensitivity of 5-fluorouracil on esophageal carcinoma in vitro and in vivo. Cancer Cell Int 2014;14(1):71. [30] Seigneuric R, Markey L, Nuyten DS, Dubernet C, Evelo CT, Finot E, et al. From nanotechnology to nanomedicine: applications to cancer research. Curr Mol Med 2010;10(7):640–52. [31] Maeda H, Wu J, Sawa T, Matsumura Y, Hori K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 2000;65(1):271–84. [32] Hu CMJ, Aryal S, Zhang L. Review Nanoparticle-assisted combination therapies for effective cancer treatment. Ther Deliv 2010;1(2):323–34. [33] Parhi P, Mohanty C, Sahoo SK. Nanotechnology-based combinational drug delivery: an emerging approach for cancer therapy. Drug Discov Today 2012;17(17–18):1044–52. [34] Brannon-peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev 2012;64:206–12.

Please cite this article in press as: Verma D et al. Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach). Med Hypotheses (2015), http://dx.doi.org/10.1016/j.mehy.2015.03.003

Nanopotentiated combination cancer therapy: Chemotherapeutic and chemosensitizer (2C approach).

An insight into the complex cancer pathophysiology reveals that a dependable amelioration of the disease could only be envisaged with a multipronged t...
217KB Sizes 0 Downloads 7 Views