Multi-faceted Environmental Bacterium is a Potential Cancer Treatment-Who Would’ve Guessed? Tumorigenesis Inhibition Due to Magnetospirillum magneticum Magnetosomes

Original Article: Alphandéry, E., Faure, S., Seksek, O., Guyot, F., Chebbi, I. 2011. Chains of magnetosomes extracted from AMB-1 magnetotactic bacteria for application in alternative magnetic field cancer therapy. ACS Nano 5(8):6279-96.

Post By: Jinglu Li and Katherine Bianchi

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                  Magnetospirillum magneticum, an aquatic, gram-negative, spiral bacterium is incredibly multi-faceted due to its usage in nanobiotechnology, magento-sensory behavior, geomicrobiology, biogeochemistry and biomineralization (Blakemore, 1975, Frankel and Bazylinski, 2004). This environmental bacterium can be used to treat various health issues via studies in tissue engineering, drug delivery, imaging, hyperthermia, and molecular diagnosis (Rodríguez- Carmona and Villaverde, 2010). It was found that these particles can also be utilized in cancer drug delivery (Rodríguez-Carmona and Villaverde, 2010).

            In the environment this bacterium has the ability to adhere to sediment, areas where there are low oxygen levels (Frankel and Bazylinski, 2004). M. magneticum orients along geomagnetic field lines (magnetotaxis) as it swims parallel or antiparallel to a magnetic field direction to search for its optimal living environment (Davila et al., 2007; Frankel & Bazylinski, 2004; Komeili et al., 2006). The magnetosome organelles within the bacterium are responsible for magnetotaxis (Frankel & Bazylinski, 2004).

            Magnetosomes consist of crystals enclosed by a lipid bilayer membrane (Frankel and Bazylinski, 2004). The magnetosomes form a chain that is parallel to the long side of the bacterium (Frankel and Bazylinski, 2004). The chain of magnetosomes make the cell behave as if it is a tiny magnetic compass needle that depends on the ratio of magnetic energy to thermal energy (Frankel & Bazylinski, 2004). Occasionally the magnetosomes form clusters instead of a chain (Frankel and Bazylinski, 2004).

Usage in Cancer Treatment:

            Due to magnetosomes’ high specific absorption rate (SAR- energy produced by radio frequency electromagnetic fields, which is absorbed by human tissue) after the introduction of an applied magnetic field (AMF), there has been increased interest in utilizing magnetosomes during magnetic hyperthermia cancer treatment (Alphandéry et al., 2012). Magnetic hyperthermia is utilized to insert nanoparticles into tumor cells, to heat the nanoparticles via AMF and to induce anti-tumor activity (Alphandéry et al., 2012). This process has been utilized in both animals and in humans in an effort to treat breast cancer, prostate cancer, head cancer, neck cancer and glioblastoma (Alphandéry et al., 2012). The method can be studied prior to clinical treatment (Rodríguez-Carmona and Villaverde, 2010).

            Recently Alphandéry et al. have conducted a series of studies that examine the effects of M. magneticum magnetosomes on breast cancer tumorigenesis. In 2011 Alphandéry et al. found that M. magneticum magnetosomes annihilates breast tumors in mice during 20 minutes of magnetic hyperthermia (Alphandéry et al., 2011). During their 2012 experiment Alphandéry et al. examined the magnetosome chains to further characterize how the chains target cancer cells, specifically epithelial cells and breast epithelial cells (Alphandéry et al., 2012). Alphandéry et al. found that not only due to the high SAR of chains of magnetosomes (CM), but also due to less particle aggregation in chains of magnetosomes (CM) compared to individual magnetosomes (IM), CM can internalize cells better.

Figure 1. Magnetosome Chains

               First, Alphandéry et al. isolated CM from the bacteria (Fig. 1a) to prevent possible toxin exposure to humans and to achieve a high yield. After isolation, those CM interacted with each other to form longer chains (Fig. 1b). After heated those CM, they obtained IM (Fig 1c, and Fig. 1d), which are more aggregated than CM either showing as an assembly of magnetosomes or in a loop. Solution mixing, sound waves and heat were used to isolate individual magnetosomes (IM) (Alphandéry et al., 2012).

            After isolation it was found that the magnetosome chains maintained connecting protein filament, whereas the filament in IM was removed (Alphandéry et al., 2012). Both chains and IM maintained the lipid bilayer (Alphandéry et al., 2012). It is possible that the lipid bilayer and the protein filament components contributed to increased cell division inhibition by CM (Alphandéry et al., 2012).  In order to test the ability of CM and IM to inhibit cancer cell proliferation, CM and IM were heated in the presence of human epithelial cells and breast cancer epithelial cells (Alphandéry et al., 2012).

            Researchers found that when CM and IM were rotated CM produced more heat, produced an increased specific absorption rate, and did not experience aggregation (unlike IM) (Alphandéry et al., 2012) (see Figure 2). However when both CM and IM did not rotate, they had similar outcomes (Alphandéry et al., 2012). Researchers predict that the magnetosome distribution and the SAR contribute to heat production (Alphandéry et al., 2012).

            Afterwards, the researchers introduced CM and IM into cancer cells (HeLa and MDA-MB-231) to see whether the application of AMF affected their ability to inhibit cancer cells. Indeed, CM had a higher inhibition than IM in both cancer cell types.Therefore CM inhibit cancer cells more efficiently.

Figure 2: Specific absorption rate (SAR) of suspensions between chains of magnetosome and individual magnetosomes with or without the application of AFM.

            CM was linked to greater magnetization. CM also had a greater stability than IM which may be linked to decreased aggregation. Due to the Prussian stain, CM appeared to be inside the tumor cells (blue stain) whereas the IM appeared to exist outside the tumor cells (no stain). The increased internalization of chains as well as lessened chain aggregation contributed to decreased tumorigenesis when magnetosome chains were utilized (Alphandéry et al., 2012). Increased maghemite in cells that were incubated with CM is linked to increased magnetism and therefore increased internalization of CM. Overall, this paper showed that CM more efficiently inhibited cancer cell proliferation under exposure to AMF. In addition, it reveals the significance of nanoparticle distribution for efficient magnetic hyperthermia.

Figure 3. A schematic summary showing the different distributions of chains of magnetosome (a) and individual magnetosomes (b) in the presence of cancer cells.

 

Possibilities for Future Studies:

            Ideally the researchers would have described the characteristics of the epithelial cells. It is unknown as to why these specific cell types were utilized during this experiment. It is also unclear as to the purpose of utilizing two epithelial strains during the experiment. A depiction of the protein filament as well as a depiction of the lipid bilayer via microscopy would have been ideal. It would be interesting to induce aggregation amongst magnetosome chains in an effort to further characterize the magnetosome chain mechanisms involved in tumorigenesis inhibition.

            It would also be advantageous to examine the effect of individual magnetosomes that retain the lipid bilayer as well as the protein filament, on tumorigenesis. Further examinations and the effects of the manipulations of the crystalline structures within the magnetosomes on tumorigenesis should be conducted. The effects of magnetosomes on different breast cancer strains as well as the effects of magnetosomes on various cancer types should be further explored.

References:

Alphandéry, E., Faure, S., Seksek, O., Guyot, F., Chebbi, I. 2011. Chains of magnetosomes extracted from AMB-1 magnetotactic bacteria for application in alternative magnetic field cancer therapy. ACS Nano 5(8):6279-96.

Alphandéry, E., Guyot, F., Chebbi, I. 2012. Preparation of chains of magnetosomes, isolated from Magnetospirillum magenticum strain AMB-1 magnetotactic bactera, yielding efficient treatment of tumors using magnetic hyperthermia. International Journal of Pharmaceutics, 434: 444-452.

Blakemore, R. 1975. "Magnetotactic bacteria". Science 190 (4212): 377–379.

Davila, A., Winklhofer, M., McKay, C. 2007. Multicellular Magnetotactic Prokaryote As a Target For Life Search On Mars. Lunar and Planetary Science XXXVIII, 2007.

Frankel, R., Bazylinski, D. 2004. Magnetosome Mysteries-Despite Reasonable Progress Elucidating Magnetotactic Microorganisms, Many Questions Remain. ASM News 70(4): 176-183.

Komeili, A., Li, Z., Newman, D., Jensen, G. 2006. Magnetosomes Are Cell Membrane Invaginations Organized by the Actin-Like Protein MamK. Science, 311:242-245.

Rodríguez-Carmona E and Villaverde A. 2010. Nanostructured bacterial materials for innovative medicines. Trends Microbiol 18(9):423-30.